CN105120859B - The method for treating melanoma - Google Patents

The method for treating melanoma Download PDF

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CN105120859B
CN105120859B CN201380075292.9A CN201380075292A CN105120859B CN 105120859 B CN105120859 B CN 105120859B CN 201380075292 A CN201380075292 A CN 201380075292A CN 105120859 B CN105120859 B CN 105120859B
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individual
melanoma
albumin
taxol
braf
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CN105120859A (en
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N·P·德赛
M·雷恩施乐
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Abraxis Bioscience LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5169—Proteins, e.g. albumin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Provided herein is the methods for the treatment of melanoma, including give including the composition containing taxane and the nano particle of carrier protein.

Description

The method for treating melanoma
Related application
This application claims 2 months 2013 U.S. Provisional Patent Application No. 61/763,391 submitted for 11st and March 8 in 2013 The priority for the U.S. Patent Application No. 13/791,841 that day submits, entire contents are incorporated by reference herein.
Technical field
The present invention relates to by giving including treating melanocyte containing the composition of taxane and the nano particle of carrier protein Method, composition and the kit of tumor.
Background of invention
Melanoma is the cancer characterized by the uncontrolled growth of pigment-producing cells (melanocyte).Chromoma is by leading The tumor conversion for being found in the melanocyte of the basal layer of epidermis and eyes develops.Spagnolo F et al., Archives of Dermatology Research,2012,304:177-184；Hurst EA et al.,Archives of Dermatology Research,2003,139:1067-1073.Chromoma is the cutaneum carcinoma of most aggressive form.Estimate It surveys 76,250 people in 2012 and is diagnosed with melanoma, and 9,180 people die of it.Spagnolo F et al.,Archives of Dermatology Research,2012,304:177-184；Surveillance Epidemiology and End (on October 6th, 2012 accesses http to Results Cancer Statistics Review 2005-2009:// seer.cancer.gov/csr/1975_2009_pops09/results_single/sect_01_table.01.pdf)。
90% cure rate, advanced melanoma is caused to resist chemotherapy although surgery removes early stage melanoma lesion, And tend to shift rapidly (Spagnolo F et al., Archives of Dermatology Research, 2012, 304:177-184)；For these reasons, the prognosis mala of advanced melanoma, wherein 5 years survival rates are respectively to suffer from the IIIA stages Person 78%, IIIB Phase patients 59% and IIIC Phase patients 40%.Balch CM et al.,Journal of Clinical Oncology,2009,27(36):6199-6206.About the patient of far-end transfer, prognosis is clearly worse, wherein 1 Year survival rate, the M1a stages be 53% in 62%, the M1b stages, and the M1c stages are only 33%.Balch CM et al., Journal of Clinical Oncology,2009,27(36):6199-6206。
The therapeutic choice of metastatic melanoma is limited.Before 2011, only two kinds of metastatic melanoma therapies are by FDA batches It is accurate：Dacarbazine and high dose interleukin-22 (" HD IL-2 "), Overall survival (median overall in position in not increasing survival).Hill G et al.,Cancer,1984,53:1299-1305；Atkins M et al.,Journal of Clinical Oncology,1999,17(7):2105-2116；Phan G et al.,Journal of Clinical Oncology,2001,19(15):3477-3482.In addition, Dacarbazine is limited by 10% to 15% low-response rate, and HD IL-2 is even with 6% to 10% more low-response rate.Finn L et al.,BMC Medicine,2012,10:23. 2011, FDA ratified two kinds of advanced melanoma therapies, the non-Buddhist nun of Wella (vemurafenib) (Zelboraf againTM) and her wood it is single Anti- (ipilimumab).Finn L et al.,BMC Medicine,2012,10:23.Although the non-Buddhist nun of Wella has been found good Clinical activity and high responsiveness and hypotoxicity, but its applicability is restricted to the following melanoma patient of 40%-60%：BRAF There is gene activated mutant, the mutation to cause a split plain activated protein kinase approach (" MAPK ") constitutive activation, cause cell Proliferation increases and oncogenic activity increases.Finn L et al.,BMC Medicine,2012,10:23.In addition, it is most of most The just Patients on Recurrence of response BRAF inhibitor for treating shows that drug resistance generates and prove only to target a kind of approach elimination melanoma Limitation.Villanueva J et al.,Cancer Cell,2010,18(6):683-695；Spagnolo F et al., Archives of Dermatology Research,2012,304:177-184.She can draw the wooden monoclonal antibody in some patientss Long-term response is played, but its availability is only made middle position time-to-live increase bimestrial by its 10% to 15% low-response rate and its Fact limitation.Finn L et al.,BMC Medicine,2012,10:23.Therefore, other therapies is still seriously needed to treat Melanoma.
All references cited herein, including patent application and publication, entire contents are incorporated by ginseng It examines.
Summary of the invention
Provided herein is the methods of individual (for example, people) melanoma for the treatment of, including give the composition of individual effective dose, the group It includes nano particle to close object, which includes taxane (for example, taxol) and carrier protein (for example, albumin). In some embodiments, melanoma is cutaneous melanoma.In some embodiments, melanoma is metastatic melanoma.One In a little embodiments, melanoma is metastatic malignant melanoma.In some embodiments, melanoma is IV stage melanoma. In some embodiments, individual has far-end transfer.In some embodiments, metastatic melanoma is in the M1a stages.At some In embodiment, metastatic melanoma is in the M1b stages.In some embodiments, metastatic melanoma is in the M1c stages.One In a little embodiments, individual suffers from measurable disease.In some embodiments, individual has brain metastes.In some embodiment party In formula, individual does not have brain metastes.In some embodiments, taxane is taxol.In some embodiments, carrier protein It is albumin, such as human serum albumins or human albumin.
In some embodiments of any method described herein, do not received melanoma therapy before individual.At some In embodiment, individual did not received the preceding cytotoxic chemotherapy for metastatic malignant melanoma.In some realities It applies in mode, individual did not received preceding auxiliary cell cytotoxic chemical therapy.In some embodiments, individual is people. In some embodiments, individual is male.In some embodiments, individual is women.In some embodiments, individual about 65 years old or less.In some embodiments, individual is at least about 65 years old (for example, any at least about 70,75 or 80 years old). In some embodiments, individual has raised serum lactic dehydrogenase (SLDH) (" LDH ") horizontal.In some embodiments, individual With normal LDH levels.In some embodiments, individual has the serum less than about 0.8 × Upper Limit of Normal Value (" ULN ") LDH.In some embodiments, individual have about 0.8 × to the Serum LDH of about 1.1 × ULN.In some embodiments, a Body has greater than about 1.1 × to the Serum LDH between about 2.0 × ULN.In some embodiments, melanoma includes wild type BRAF.In some embodiments, melanoma includes the mutation of BRAF.In some embodiments, melanoma includes BRAF's V600E is mutated.
In some embodiments of any method described herein, including contain taxane (for example, taxol) and carrier The composition of the nano particle of albumen (for example, albumin) is used as the monotherapy for the treatment of melanoma.In any side described herein In some embodiments of method, method further comprises the second therapy.In some embodiments, the second therapy is selected from chemistry and treats Method, immunotherapy, operation, radiotherapy, targeted therapies or combinations thereof.In some embodiments, method includes giving at least A kind of other therapeutic agents.In some embodiments, a kind of other therapeutic agents are BRAF inhibitor.In some embodiments, A kind of other therapeutic agents are her wooden monoclonal antibodies.In some embodiments, this method is used as the first gamma therapy.In some embodiment party In formula, this method is used as the second gamma therapy.
In some embodiments of any method described herein, including contain taxane (for example, taxol) and carrier The composition of albumen (for example, albumin) nano particle is by intravenous administration.In some embodiments, Nanoparticulate compositions The dosage of middle taxane (for example, taxol) is about 50mg/m2To about 400mg/m2.In some embodiments, nano particle group The dosage for closing taxane (for example, taxol) in object is about 100mg/m2To about 200mg/m2.In some embodiments, nanometer The dosage of taxane (for example, taxol) is about 150mg/m in particulate composition2.In some embodiments, including contain purple The Nanoparticulate compositions of China fir alkane (for example, taxol) and carrier protein (for example, albumin) are given weekly.In some implementations In mode, method includes at least one 28 days treatment cycles.In some embodiments, including contain taxane (for example, Japanese yew Alcohol) and carrier protein (for example, albumin) nano particle composition the 1st, 8 and 15 day of 28 days treatment cycles by It gives.In some embodiments, carrier protein is albumin.In some embodiments, albumin is human serum albumins. In some embodiments, albumin is human albumin.In some embodiments, albumin is recombinant albumin.In some realities It applies in mode, the average diameter of the nano particle in composition is not greater than about 200nm.In some embodiments, nano particle The weight ratio of albumin and taxane (for example, taxol) is about 9 in composition：1 or smaller.In some embodiments, it receives The weight ratio of albumin and taxane (for example, taxol) is about 9 in rice grain composition：1.In some embodiments, it receives Taxane (for example, taxol) in rice grain is coated with albumin.In some embodiments, taxane is taxol. In some embodiments, the method that the melanoma for the treatment of individual (for example, people) is provided, including give individual effective dose includes containing There is the composition of the nano particle of taxol and albumin (for example, human albumin or human serum albumins).
In some embodiments, the method that treatment individual human melanoma is provided, including give individual effective dose includes The composition of nano particle containing taxol and albumin.In some embodiments, individual is based on to shift with the M1c stages Property melanoma selects individual to be treated.In some embodiments, being based on individual has greater than about 1.1 × to about 2.0 × Serum LDH level between ULN selects individual to be treated.In some embodiments, it is based on individual to suffer from including wild The melanoma of type BRAF selects individual to be treated.In some embodiments, based on individual with the mutation for including BRAF The melanoma of the V600E of such as BRAF (be mutated) selects individual to be treated.
In some embodiments, method further comprises the second therapy, for example, the second therapy includes giving at least one Other therapeutic agents.In some embodiments, other therapeutic agents are BRAF inhibitor.In some embodiments, other treatment Agent is her wooden monoclonal antibody.
In some embodiments, this method is used as the first gamma therapy.In some embodiments, this method is used as second Gamma therapy.
In some embodiments, include the nano particle containing taxol and albumin composition by intravenously to It gives.In some embodiments, the dosage of taxol is about 80mg/m in Nanoparticulate compositions2To about 200mg/m2(for example, About 150mg/m2).In some embodiments, include the nano particle containing taxol and albumin composition by weekly to It gives, for example, the 1st, 8 and 15 day in 28 days treatment cycles is given.
In some embodiments, albumin is human serum albumins.In some embodiments, nanometer in composition The average diameter of grain is not greater than about 200nm.In some embodiments, in Nanoparticulate compositions albumin and taxol weight It is about 9 to measure ratio：1 or smaller.In some embodiments, the taxol in nano particle is coated with albumin.
In some embodiments, kit is provided comprising (i) includes the nano particle containing taxol and albumin Composition, and (ii) give Nanoparticulate compositions to treat the explanation of melanoma.
It is appreciated that one in the property of various embodiments described herein, some or all properties may be combined to form this The other embodiment of invention.It will be obvious to those skilled in the art for these and other aspects of the invention.
Brief description
Fig. 1 display Nab- taxols (or) Dacarbazine is compared in the pernicious melanocyte of metastatic without chemotherapy The research and design that the III phases in tumor patient are studied.DCR, disease control rate；ECOG, east tumour cooperative groups (Eastern Cooperative Oncology Group)；LDH, lactic dehydrogenase；ORR, objective responsiveness；OS, Overall survival；PFS, nothing It is in progress life cycle；RECIST, the response evaluation criterion of entity tumor；ULN, Upper Limit of Normal Value.
Fig. 2 shows the progression free survival phase checked by separate radiation.Nab- taxols (or) group PFS：4.8 months；The PFS of Dacarbazine group：2.5 months (P=0.044).CI, confidence interval；HR, hazard ratio.
The Overall survival plan interim analysis of Fig. 3 display researchs.Nab- taxols (or) group middle position OS： 12.8 a month；The middle position OS of Dacarbazine group：10.7 a month.* indicate that 64% patient has event when PFS is analyzed.
Fig. 4 shows the Overall survival interim analysis of specific subgroup.
Detailed description of the invention
Provided herein is the melanocytes using the composition treatment individual for including the nano particle containing taxane and carrier protein The method of tumor (for example, IV stages or metastatic cutaneous melanoma).
Using the stabilized taxol of albumin nanoparticle formulations (Nab- taxols or) comparison Dacca The III phases of bar piperazine are studied to carry out in the metastatic malignant melanoma patient without chemotherapy.Dacarbazine be only one from Chemotherapy by FDA approvals for metastatic melanoma in 1975.Studies have shown thatMake compared with Dacarbazine Progression free survival phase (" PFS ") almost double (PFS：It is 4.8 months, and Dacarbazine is 2.5 months, P= 0.044)。It is first single medicine chemotherapy confirmed relative to the statistically significant raising of Dacarbazine over 37 years. Therefore the present invention provides through give including the composition containing taxane and the nano particle of carrier protein come treat individual it is black Method, composition and the kit of plain tumor.
In some embodiments, the method that treatment autologous melanoma is provided, including it includes containing taxane to give individual With the composition of the nano particle of carrier protein.In some embodiments, individual has IV stages or metastatic melanoma (example Such as, IV stages or metastatic cutaneous melanoma).In some embodiments, melanoma is metastatic malignant melanoma.At some In embodiment, metastatic melanoma is in M1a stages, M1b stages or M1c stages.In some embodiments, metastatic melanocyte Tumor is in the M1c stages.In some embodiments, melanoma includes the mutation of BRAF.In some embodiments, melanoma is not wrapped Include the mutation of BRAF.In some embodiments, melanoma does not include BRAF mutant, and such as activity increases (for example, kinase activity Increase and/or with wild type BRAF compared with activity increase) BRAF mutant or the enhanced mutant of BRAF functions.In some realities It applies in mode, melanoma does not include BRAF V600E mutation (for example, melanoma includes wild type BRAF).In some embodiments In, melanoma includes BRAF mutant, and such as activity increases (for example, kinase activity increases and/or the activity compared with wild type BRAF Increase) BRAF mutant or the enhanced mutant of BRAF functions.In some embodiments, melanoma includes BRAF V600E Mutation.In some embodiments, individual has raised serum lactic dehydrogenase (SLDH) (" LDH ") level (for example, and normal level It is horizontal to compare raised LDH for normal LDH level or the normal LDH level without melanoma or cancer individual as known in the art). In some embodiments, individual has normal Serum LDH horizontal.In some embodiments, individual, which has, is less than about 0.8 The Serum LDH of × Upper Limit of Normal Value (" ULN ").In some embodiments, individual have about 0.8 × to the blood of about 1.1 × ULN Clear LDH.In some embodiments, individual have greater than about 1.1 × to the Serum LDH between about 2.0 × ULN.In some realities It applies in mode, individual has about 1.1 × to the Serum LDH between about 2.0 × ULN.In some embodiments, individual is people (for example, sex).In some embodiments, taxane is taxol.In some embodiments, carrier protein is Albumin.
Be also provided herein the composition (such as pharmaceutical composition) that can be used for methods described herein, product, drug, kit and Unit dose.Certain combination therapies, kit and the composition for treating melanoma is also provided herein.
Definition
Term " individual " refers to mammal, including people.Individual includes but not limited to people, ox, horse, cat class, canine, grinding tooth Class or primate.In some embodiments, individual is people.Term " individual " further includes the people patient described in embodiment.
As used herein, " treatment " is to obtain the approach of beneficial or desired clinical effectiveness.Beneficial or desired clinical knot Fruit may include but be not limited to it is following in any one or more：One or more symptoms mitigate, disease degree reduces, disease shape State stablizes (that is, not deteriorating), prevents or postpone disease's spread (for example, transfer), prevent or postpone disease generation or repeatedly, disease (no matter partly or entirely) progress postpones or slows down, morbid state improves and alleviate." treatment " further includes proliferative disease such as cancer The pathological consequences of disease (for example, melanoma) are reduced.Method provided herein consider in terms of these treatments in any one or it is more It is a.
The term as used herein " effective quantity " reference be enough to treat when the second therapy alone or in combination is applied specified obstacle, Situation or disease such as improve, mitigate, reduce and/or postpone one or more compound or composition amounts of its symptom.About Cancer or other unwanted cells proliferation, effective quantity include being enough to lead to tumor shrinkage and/or reducing tumor growth rate (such as Inhibit tumour growth) prevent or postpone other unwanted cells proliferation amount.Effective quantity can in single or divided doses by It gives.In the case of melanoma, a effective amount of drug or composition can：(i) melanoma cells quantity is reduced；(ii) reduce black The tumor size of plain tumor；(iii) inhibit to a certain extent, hinder, slowing down and for example, melanoma cells being prevented to infiltrate to surrounding In organ；(iv) inhibit the metastases of (that is, slow down to a certain extent and for example prevent) melanoma；(v) inhibit melanoma Tumour growth；(vi) prevent or postpone melanoma occur and/or repeatedly；And/or (vii) alleviates to a certain extent and melanocyte It is one or more in the relevant symptom of tumor.
As used herein, " combined therapy " means that combining other agent for first dose is given." joint " is referred in a kind for the treatment of Other treatment mode is also given except mode, such as also gives same individual except Nanoparticulate compositions as described herein giving Other agent.Therefore, " joint " reference is given delivers other treatment side before, during or after a kind of therapeutic modality to individual Formula.
As used herein, " pharmaceutically acceptable " or " pharmacology is compatible " mean material not and be biology or other Mode is undesirable, for example, material can be impregnated in the pharmaceutical composition for giving individual or patient, without cause it is any it is significant not Desired biological effect or any one of the other components for not including with composition are interacted in a manner of bad.Pharmaceutically Acceptable carrier or excipient for example meet toxicology and the required standard of production test, and/or are included in U.S.'s food Inactive Ingredient Guide (the Inactive made with Drug Administration (U.S.Food and Drug administration) Ingredient Guide) in.
As herein and used in the appended claims, singulative "one", "an" and " described " include plural reference, Unless the clear in addition instruction of context.
" about " reference of numerical value or parameter includes that (and description) is directed to the embodiment of the numerical value or parameter itself herein.Example Such as, the description as described in " about X " includes the description of " X ".
It is appreciated that invention as described herein aspect and modification include " being made of aspect or modification " and/or " mainly by Aspect and modification composition ".
The method for treating melanoma
The present invention, which provides, utilizes the individual (example of composition treatment for including the nano particle containing taxane and carrier protein Such as, people) melanoma method.
In some embodiments, melanoma is cutaneous melanoma.In some embodiments, melanoma is that metastatic is black Plain tumor.In some embodiments, melanoma is metastatic malignant melanoma.In some embodiments, melanoma is IV ranks Section melanoma (for example, IV stages cutaneous melanoma).In some embodiments, metastatic melanoma is in the M1a stages.At some In embodiment, metastatic melanoma is in the M1b stages.In some embodiments, metastatic melanoma is in the M1c stages.One In a little embodiments, individual did not received the preceding therapy for melanoma (for example, metastatic melanoma) (for example, preceding Cytotoxic chemotherapy).In some embodiments, melanoma includes the mutation of BRAF.In some embodiments, black Plain tumor includes BRAF V600E mutation.In some embodiments, melanoma does not include the mutation of BRAF (for example, melanoma packet Include wild type BRAF).In some embodiments, melanoma does not include BRAF mutant, and such as activity increases (for example, kinases is lived Property increase and/or with wild type BRAF compared with activity increase) BRAF mutant or the enhanced mutant of BRAF functions.At some In embodiment, melanoma does not include constitutive activity BRAF mutant.In some embodiments, melanoma does not include BRAF V600E is mutated (for example, melanoma includes wild type BRAF).In some embodiments, melanoma includes wild type BRAF (examples Such as, melanoma cells have wild type BRAF).In some embodiments, melanoma includes BRAF mutant, and such as activity increases The BRAF mutant or BRAF functions of (for example, kinase activity increases and/or activity increases compared with wild type BRAF) are enhanced Mutant.In some embodiments, melanoma includes constitutive activity BRAF mutant.In some embodiments, melanocyte Tumor includes BRAF V600E mutation.In some embodiments, individual has raised serum lactic dehydrogenase (SLDH) (" LDH ") water It is flat.In some embodiments, individual has the Serum LDH less than about 0.8 × Upper Limit of Normal Value (" ULN ").In some implementations In mode, individual has about 0.8 × to the Serum LDH of about 1.1 × ULN.In some embodiments, individual has greater than about 1.1 × to the Serum LDH between about 2.0 × ULN.In some embodiments, individual have about 1.1 × to about 2.0 × ULN it Between Serum LDH.In some embodiments, individual was at about 65 years old or less.In some embodiments, individual is at least about 65 Year (for example, at least about any of 70,75 or 80 years old).In some embodiments, individual is male.In some embodiment party In formula, individual is women.In some embodiments, individual has one in the patient characteristic that the embodiment of the present disclosure 1 and 2 describes It is a or multiple.For example, individual can have at least one of following features (for example, any at least 2,3,4,5,6 or 7 Kind)：(1) skin malignant melanoma that histology or cytology confirm, there is transfer sign (IV stages)；(2) it is directed to without preceding The cytotoxic chemotherapy of metastatic malignant melanoma；(3) without preceding auxiliary cell cytotoxic chemical therapy；(4) male or Non-pregnancy and non-lactation period women, >=18 years old；(5) the malignant tumour activity without other current actives in past 3 years；(6) it puts Penetrate the measurability disease (for example, surveying lesion there are at least one recorded radiation image) of photologging；(7) ECOG is showed State 0-1.In some embodiments, individual does not have brain metastes medical history or current sign, including leptomeninges involves.In some realities Apply in mode, individual do not suffer from pre-exist >=peripheral nerve disease of 2 grades of NCI CTCAE.
In some embodiments, melanoma is cutaneous melanoma.In some embodiments, melanoma is the black pigment of skin Tumor.In some embodiments, melanoma is superficial diffusion melanoma.In some embodiments, melanoma is tubercle melanocyte Tumor.In some embodiments, melanoma is acral-lentiginous melanoma.In some embodiments, melanoma is pernicious Lentigo melanoma.In some embodiments, melanoma be mucosal melanoma (for example, nose, mouth, the areas Hou Huoxing mucous membrane melanocyte Tumor).In some embodiments, melanoma is ophthalmomelanoma.In some embodiments, melanoma is uveal melanoma. In some embodiments, melanoma is choroidal melanoma.For example, in some embodiments, providing treatment individual (example Such as, people) cutaneous melanoma (for example, metastatic or IV stages cutaneous melanoma) method, including give individual include containing purple The composition of the nano particle of China fir alkane (for example, taxol) and carrier protein (for example, albumin).In some embodiments, Individual has IV stages or metastatic melanoma.In some embodiments, melanoma is metastatic malignant melanoma.At some In embodiment, metastatic melanoma is in M1a stages, M1b stages or M1c stages.In some embodiments, metastatic melanocyte Tumor is in the M1c stages.In some embodiments, melanoma includes the mutation of BRAF.In some embodiments, melanoma is not wrapped Include the mutation of BRAF.In some embodiments, melanoma does not include BRAF mutant, and such as activity increases (for example, kinase activity Increase and/or with wild type BRAF compared with activity increase) BRAF mutant or the enhanced mutant of BRAF functions.In some realities It applies in mode, melanoma does not include constitutive activity BRAF mutant.In some embodiments, melanoma does not include BRAF V600E is mutated (for example, melanoma includes wild type BRAF).In some embodiments, melanoma includes wild type BRAF (examples Such as, melanoma cells have wild type BRAF).In some embodiments, melanoma includes BRAF mutant, and such as activity increases The BRAF mutant or BRAF functions of (for example, kinase activity increases and/or activity increases compared with wild type BRAF) are enhanced Mutant.In some embodiments, melanoma includes BRAF V600E mutation.In some embodiments, melanoma includes Constitutive activity BRAF mutant.In some embodiments, melanoma does not include constitutive activity BRAF mutant.At some In embodiment, used as monotherapy using the method that taxane nano particle treats melanoma.In some embodiments In, do not further comprise that other therapeutic agents (such as other chemotherapeutics or are exempted from using the method that taxane nano particle treats melanoma Epidemic disease therapeutic agent).In some embodiments, method does not further comprise cytotoxic chemotherapeutic agent.
Melanoma as described herein can be any one of following：Cutaneous melanoma, skin outer melanoma, superficial diffusivity Melanoma, chromoma, tubercle chromoma, tubercle melanoma, polypoid melanoma, acral lentiginous melanin Tumor, lentiginous chromoma, amelanotic melanoma, lentigo maligna melanoma, mucous membrane lentiginous melanoma, mucous membrane Melanoma, ophthalmomelanoma, promotees desmoplastic melanoma or metastatic malignant melanoma at soft tissue melanoma.
In some embodiments, melanoma to be treated is stage 0, stage I, stage II, stage III or stage IV. In some embodiments, melanoma to be treated be the stage 0, stage IA, stage IB, stage IIA, stage IIB, stage IIC, Stage IIIA, stage IIIB, stage IIIC or stage IV.In some embodiments, melanoma is metastatic melanoma.One In a little embodiments, metastatic melanoma is in the M1a stages.In some embodiments, metastatic melanoma is in the M1b stages. In some embodiments, metastatic melanoma is in the M1c stages.Melanoma can be based on side well known by persons skilled in the art by stages Method.Melanoma by stages can according to 2009AJCC melanoma by stages with classification (2009AJCC Melanoma Staging and Classification the standard for) including.Referring to Balch CM et al., J Clin Oncol.2009,27 (36):6199- 206 (the disclosure of which is all hereby incorporated by reference).For example, melanoma by stages can be listed according to table 1 and 2 Standard.
The TNM stage classification of 1. cutaneous melanoma of table
Abbreviation：NA is not suitable for；LDH, lactic dehydrogenase.
* micro transfer is diagnosed after piedmont belts.
A large amount of transfers are defined as the tubercle transfer that clinical detectable pathology confirm.
The anatomy stage of 2. cutaneous melanoma of table is grouped
* clinical stages includes the microstaging of primary melanoma and clinic/radiological evaluation of transfer.By converting, It should be used to cut off completely together with clinical assessment region and far-end transfer after primary melanoma.
Pathological staging include primary melanoma microstaging and about part (that is, the biopsy of outpost's tubercle) Or the pathological information of the postoperative regional lymph nodes of complete lymph node resection.0 stage of pathology or IA Phase patients are exceptions；It is not Need the pathological evaluation about its lymph node.
In some embodiments, melanoma is early stage melanoma (for example, early stage cutaneous melanoma).One In a little embodiments, melanoma is later stage melanoma (for example, later stage cutaneous melanoma).In some embodiments, melanoma It is advanced melanoma.In some embodiments, individual suffers from measurable disease.In some embodiments, melanoma is to turn Shifting property melanoma (for example, metastatic cutaneous melanoma).In some embodiments, melanoma is metastatic malignant melanoma (for example, the pernicious cutaneous melanoma of metastatic).In some embodiments, melanoma is IV stages melanoma (for example, the IV stages Cutaneous melanoma).In some embodiments, individual suffers from measurable disease.Measurable disease can utilize people in the art Method known to member determines.In some embodiments, measurable disease refers to surveying there are at least one recorded radiation image Lesion.In some embodiments, melanoma is the melanoma for having in brain one or more metastatics site.
In some embodiments, melanoma is non-metastatic melanoma.In some embodiments, melanoma is transfer Property melanoma.In some embodiments, melanoma is primary melanoma.In some embodiments, primary melanoma It has shifted.In some embodiments, melanoma is Locally Advanced melanoma.In some embodiments, melanoma is repeatedly Melanoma.In some embodiments, melanoma after alleviation repeatedly.In some embodiments, melanoma is that progressive is black Plain tumor.In some embodiments, melanoma is the melanoma in alleviating.In some embodiments, individual has far-end transfer. Far-end transfer can be based on methods known in the art, and can be referred to distal end skin, the transfer of subcutaneous or tubercle or remote organ Transfer such as Lung metastases.In some embodiments, individual does not have far-end transfer.In some embodiments, individual has office Portion's cutaneous metastatic.In some embodiments, individual has distal end skin, the transfer of subcutaneous or tubercle.In some embodiments, Individual has visceral metastases.In some embodiments, individual does not have visceral metastases.In some embodiments, individual tool There are lung, liver, bone or the brain metastes of melanoma.In some embodiments, individual does not have the brain metastes of melanoma.In some realities It applies in mode, melanoma is that localization is resectable, localization is unresectable or unresectable.In some embodiments In, received BRAF inhibitor for treating before individual, e.g., for example, the non-Buddhist nun of Wella (Zelboraf) or Sorafenib (Nexavar)。
For example, providing the side of the IV stages melanoma (for example, IV stages cutaneous melanoma) for the treatment of individual (for example, people) Method, including it includes the nano particle containing taxane (for example, taxol) and carrier protein (for example, albumin) to give individual Composition.In some embodiments, the metastatic melanoma for the treatment of individual (for example, people) is provided (for example, metastatic skin is black Plain tumor) (such as melanoma in metastatic M1a, M1b or M1c stages) method, including give individual include contain taxane (example Such as, taxol) and carrier protein (for example, albumin) nano particle composition.In some embodiments, metastatic is black Plain tumor is in any one of M1a stages, M1b stages or M1c stages.In some embodiments, provide treatment individual (example Such as, people) the metastatic M1c stages metastatic cutaneous melanoma method, including give individual include contain taxane (example Such as, taxol) and carrier protein (for example, albumin) nano particle composition.In some embodiments, melanoma packet Include the mutation of BRAF.In some embodiments, melanoma does not include the mutation of BRAF.In some embodiments, melanoma Do not include BRAF mutant, as activity increases (for example, kinase activity increases and/or activity increases compared with wild type BRAF) BRAF mutant or the enhanced mutant of BRAF functions.In some embodiments, melanoma does not include BRAF V600E mutation (for example, melanoma includes wild type BRAF).In some embodiments, melanoma includes wild type BRAF.In some implementations In mode, melanoma includes BRAF mutant, and such as activity increases (for example, kinase activity increases and/or compared with wild type BRAF Activity increase) BRAF mutant or the enhanced mutant of BRAF functions.In some embodiments, melanoma includes BRAF V600E is mutated.In some embodiments, made as monotherapy using the method that taxane nano particle treats melanoma With.In some embodiments, do not further comprise other therapeutic agents using the method that taxane nano particle treats melanoma (such as other chemotherapeutics or immunotherapeutic agent).In some embodiments, method does not further comprise cytotoxic chemotherapeutic agent.
In some embodiments, there is individual melanoma, thickness to be less than about 0.5 millimeter (" mm "), 1mm, 1.5mm, Any of 2mm, 2.5mm, 3mm, 3.5mm, 4mm, 4.5mm, 5mm, 5.5mm, 6mm, 6.5mm, 7mm, 7.5mm or 8mm. In some embodiments, individual have melanoma, thickness be at least about 0.5mm, 1mm, 1.5mm, 2mm, 2.5mm, 3mm, Any of 3.5mm, 4mm, 4.5mm, 5mm, 5.5mm, 6mm, 6.5mm, 7mm, 7.5mm or 8mm.In some embodiments In, individual has melanoma, thickness is about 0.5mm, 1mm, 1.5mm, 2mm, 2.5mm, 3mm, 3.5mm, 4mm, 4.5mm, Any of 5mm, 5.5mm, 6mm, 6.5mm, 7mm, 7.5mm or 8mm.In some embodiments, individual has melanoma, Its thickness is about 0-1mm, 1-2mm, 2-3mm, 3-4mm, 4-5mm, 5-6mm, 1-4mm, 1-6mm, 2-4mm, 2-6mm or 4-6mm Any of.
Any individual with melanoma (for example, metastatic melanoma, such as metastatic cutaneous melanoma) can use this paper institutes Method is stated to treat.In some embodiments, individual did not received without chemotherapy or regimen chemotherapy.In some embodiment party In formula, do not received the treatment for melanoma before individual.In some embodiments, do not received to be directed to before individual to turn The treatment of shifting property melanoma.In some embodiments, individual did not received for melanoma (for example, the pernicious melanocyte of metastatic Tumor) in preceding therapy or at preceding chemotherapy (such as preceding cytotoxic chemotherapy).In some embodiments, individual not Received preceding complementary therapy (for example, auxiliary cell cytotoxic chemical therapy).In some embodiments, it is not connect before individual Kinase inhibitor for treating is received.In some embodiments, do not received cytokine therapy before individual.In some embodiment party In formula, complementary therapy (for example, interferon, GM-CSF or vaccine) treatment was not received before individual.For example, providing treatment individual The method of the melanoma (for example, metastatic cutaneous melanoma) of (for example, people), including it includes containing taxane (example to give individual Such as, taxol) and carrier protein (for example, albumin) nano particle composition, wherein individual do not received be directed to melanocyte Tumor in preceding therapy or at preceding chemotherapy (such as preceding cytotoxic chemotherapy).In some embodiments, melanoma Mutation including BRAF.In some embodiments, melanoma does not include the mutation of BRAF.In some embodiments, melanocyte Tumor does not include BRAF mutant, and such as activity increases (for example, kinase activity increases and/or activity increases compared with wild type BRAF) BRAF mutant or the enhanced mutant of BRAF functions.In some embodiments, melanoma does not include BRAF V600E prominent Become (for example, melanoma includes wild type BRAF).In some embodiments, melanoma includes wild type BRAF.In some realities Apply in mode, melanoma includes BRAF mutant, such as activity increase (for example, kinase activity increase and/or with wild type BRAF phases Specific activity increase) BRAF mutant or the enhanced mutant of BRAF functions.In some embodiments, melanoma includes BRAF V600E is mutated.In some embodiments, made as monotherapy using the method that taxane nano particle treats melanoma With.In some embodiments, do not further comprise other therapeutic agents using the method that taxane nano particle treats melanoma (such as other chemotherapeutics or immunotherapeutic agent).In some embodiments, method does not further comprise cytotoxic chemotherapeutic agent.
It is any to have normal or raised lactic dehydrogenase (" LDH ") horizontal (such as normal or raised Serum LDH is horizontal) Individual can be treated with methods described herein.In some embodiments, individual has normal LDH levels, such as normal serum LDH levels (for example, normal Serum LDH baseline level or normal Serum LDH when being diagnosed to be melanoma).In some implementations In mode, individual has raised LDH horizontal, and such as raised Serum LDH is horizontal (for example, raised when being diagnosed to be melanoma Serum LDH baseline level or raised Serum LDH).In some embodiments, individual has notable raised Serum LDH water It is flat.In some embodiments, individual has with normal serum LDH value or increases compared with the serum LDH value without melanoma individual At least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, Any Serum LDH is horizontal in 175% or 200%.Serum LDH level can be utilized known in the art by those skilled in the art Method determine.In some embodiments, Serum LDH level can be determined by immunoassays, for example, ELISA or sandwich ELISA.In some embodiments, Serum LDH level can be determined by colorimetric estimation, wherein passing through absorbance under 340nm Variation monitoring NAD+ reduction (lactate is oxidized to acetone acid group) or NADH oxidation (acetone acid group is reduced into lactate). In some embodiments, LDH levels can be determined using the LDH activity dyeing that adds lustre to by electrophoresis.In some embodiments, It is horizontal that LDH levels as described herein refer to baseline LDH.In some embodiments, LDH levels reference as described herein is diagnosing LDH when going out melanoma is horizontal.In some embodiments, LDH levels as described herein, which refer to, is being diagnosed to be the IV stages or is turning LDH when shifting property melanoma is horizontal.In some embodiments, LDH levels as described herein are compared with no melanoma individual Compared with.In some embodiments, LDH levels and normal LDH level known in the art or the LDH without melanoma or cancer individual It is raised that level, which is compared,.In some embodiments, LDH levels and normal LDH level range known in the art or health It is raised that the LDH levels of individual, which are compared,.In some embodiments, LDH levels refer to horizontal (the LDH isodynamic enzymes combinations of total LDH Together).
In some embodiments, individual have at least about 0.6 × Upper Limit of Normal Value (" ULN "), 0.7 × ULN, 0.8 × ULN、0.9×ULN、1.0×ULN、1.1×ULN、1.2×ULN、1.3×ULN、1.4×ULN、1.5×ULN、1.6×ULN、 The Serum LDH of any of 1.7 × ULN, 1.8 × ULN, 1.9 × ULN, 2.0 × ULN, 2.1 × ULN or 2.2 × ULN are horizontal. In some embodiments, individual have below about 0.6 × ULN, 0.7 × ULN, 0.8 × ULN, 0.9 × ULN, 1.0 × ULN, 1.1×ULN、1.2×ULN、1.3×ULN、1.4×ULN、1.5×ULN、1.6×ULN、1.7×ULN、1.8×ULN、1.9× ULN、2.0×ULN、2.1×ULN、2.2×ULN、2.3×ULN、2.4×ULN、2.5×ULN、2.6×ULN、2.7×ULN、 The Serum LDH of any of 2.8 × ULN or 3.0 × ULN is horizontal.In some embodiments, individual have about 0.6 × ULN, 0.7×ULN、0.8×ULN、0.9×ULN、1.0×ULN、1.1×ULN、1.2×ULN、1.3×ULN、1.4×ULN、1.5× Any of ULN, 1.6 × ULN, 1.7 × ULN, 1.8 × ULN, 1.9 × ULN, 2.0 × ULN, 2.1 × ULN or 2.2 × ULN's Serum LDH is horizontal.In some embodiments, individual have about 0.4 × ULN -0.8 × ULN, 0.6 × ULN-2.5 × ULN, 0.8×ULN-2.0×ULN、0.8×ULN–1.5×ULN、0.8×ULN–1.2×ULN、0.8×ULN–1.1×ULN、0.9× ULN–1.1×ULN、0.8×ULN–1.2×ULN、1.0×ULN–2.2×ULN、1.1×ULN–2.0×ULN、>1.1×ULN– 2.0×ULN、>1.2×ULN–2.0×ULN、1.2×ULN–2.2×ULN、1.2×ULN–2.0×ULN、1.5×ULN–2.0 ×ULN、1.2×ULN–5.0×ULN、1.2×ULN–4.0×ULN、2.0×ULN–4.0×ULN、1.2×ULN–3.5× ULN、1.2×ULN–3.0×ULN、1.2×ULN–2.5×ULN、1.1×ULN–1.8×ULN、1.1×ULN–1.5×ULN、 The Serum LDH of any of 1.2 × ULN -1.5 × ULN, 1.2 × ULN -1.8 × ULN or 1.3 × ULN -1.8 × ULN is horizontal. In some embodiments, individual has the Serum LDH less than about 0.8 × Upper Limit of Normal Value (" ULN ").In some embodiments In, individual has about 0.8 × to the Serum LDH of about 1.1 × ULN.In some embodiments, individual have greater than about 1.1 × Serum LDH to about 2.0 × ULN.In some embodiments, individual have about 1.1 × between about 2.0 × ULN Serum LDH.For example, the method that the melanoma (for example, metastatic cutaneous melanoma) for the treatment of individual (for example, people) is provided, including The composition that individual includes the nano particle containing taxane (for example, taxol) and carrier protein (for example, albumin) is given, Wherein individual has normal Serum LDH horizontal.In some embodiments, melanoma is metastatic malignant melanoma.One In a little embodiments, metastatic melanoma is in M1a stages, M1b stages or M1c stages.In some embodiments, metastatic is black Plain tumor is in the M1c stages.In some embodiments, melanoma includes the mutation of BRAF.In some embodiments, melanoma is not Mutation including BRAF.In some embodiments, melanoma does not include BRAF mutant, and such as activity increases (for example, kinases is lived Property increase and/or with wild type BRAF compared with activity increase) BRAF mutant or the enhanced mutant of BRAF functions.At some In embodiment, melanoma does not include BRAF V600E mutation (for example, melanoma includes wild type BRAF).In some embodiment party In formula, melanoma includes wild type BRAF.In some embodiments, melanoma includes BRAF mutant, and such as activity increases (example Such as, kinase activity increase and/or with wild type BRAF compared with activity increase) BRAF mutant or the enhanced mutation of BRAF functions Body.In some embodiments, melanoma includes BRAF V600E mutation.In some embodiments, individual be people (for example, Sex).In some embodiments, taxane is taxol.In some embodiments, carrier protein is white egg In vain.In some embodiments, it is used as monotherapy using the method that taxane nano particle treats melanoma.At some In embodiment, do not further comprise that (such as other change other therapeutic agents using the method that taxane nano particle treats melanoma Treat agent or immunotherapeutic agent).In some embodiments, method does not further comprise cytotoxic chemotherapeutic agent.
For another example the method for providing the melanoma (for example, metastatic cutaneous melanoma) for the treatment of individual (for example, people), packet Include the combination for giving that individual includes the nano particle containing taxane (for example, taxol) and carrier protein (for example, albumin) Object, wherein individual has raised Serum LDH horizontal.In some embodiments, individual has the serum of following one of which LDH：Serum LDH less than about 0.8 × ULN is horizontal, about 0.8 × to about 1.1 × ULN Serum LDH it is horizontal or greater than about 1.1 × Serum LDH to about 2.0 × ULN.In some embodiments, individual have IV stages or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma).In some embodiments, melanoma is metastatic malignant melanoma.In some realities It applies in mode, metastatic melanoma is in M1a stages, M1b stages or M1c stages.In some embodiments, metastatic melanoma In the M1c stages.In some embodiments, melanoma includes the mutation of BRAF.In some embodiments, melanoma includes group Constitutive active BRAF mutant.In some embodiments, melanoma includes BRAF mutant, and such as activity increases (for example, kinases Activity increase and/or with wild type BRAF compared with activity increase) BRAF mutant or the enhanced mutant of BRAF functions.One In a little embodiments, melanoma includes BRAF V600E mutation.In some embodiments, individual is people (for example, male or female Property).In some embodiments, taxane is taxol.In some embodiments, carrier protein is albumin.At some In embodiment, used as monotherapy using the method that taxane nano particle treats melanoma.In some embodiments In, do not further comprise that other therapeutic agents (such as other chemotherapeutics or are exempted from using the method that taxane nano particle treats melanoma Epidemic disease therapeutic agent).In some embodiments, method does not further comprise cytotoxic chemotherapeutic agent.
BRAF is the protein encoded by BRAF gene.The gene is also referred to as proto-oncogene B-Raf and v-Raf mouse Sarcoma virus oncogene homologue B1.The mutation of BRAF has been accredited in melanoma, including codon 600 mutation (for example, From valine to glutamic acid mutation at codon 600).It is referred to as V599E before V600E mutation to be mutated, and the sequence based on supplement Row data is renamed.Referring to Davies H et al., Nature 2002,417:949-54.In methods described herein In some embodiments, melanoma includes wild type BRAF (for example, melanoma cells have wild type BRAF).In some implementations In mode, melanoma includes the mutation of BRAF.In some embodiments, melanoma does not include the mutation of BRAF.In some realities It applies in mode, melanoma includes the mutation in BRAF at codon 600 (such as Val is mutated into Glu, Asp, Lys or Arg).One In a little embodiments, melanoma does not include the V600E mutation of BRAF (for example, melanoma cells are that BRAF V600E mutation are negative ).In some embodiments, melanoma includes BRAF V600E mutation.In some embodiments, melanoma cells are with pure V600E BRAF gene types are closed to be characterized.In some embodiments, melanoma cells are with heterozygosis V600E BRAF gene types Feature.In some embodiments, the mutation of BRAF can be determined by the real-time PCR of allele-specific.In some embodiment party In formula, the mutation of BRAF can be determined by converting end experiment (shifted termination assay, STA).At some In embodiment, the mutation of BRAF can be determined by nucleic acid sequencing.In some embodiments, the mutation of BRAF can utilize commercially available Kit determines, is such as purchased from such as kit of Roche, Neogenomics, Lab 2 or other companies.
In some embodiments, melanoma does not include BRAF mutant, and such as activity increases or raised BRAF mutant (for example, kinase activity increases and/or activity increases compared with wild type BRAF) or the enhanced mutant of BRAF functions.At some In embodiment, melanoma does not include constitutive activity BRAF mutant.In some embodiments, melanoma does not include BRAF V600E is mutated (for example, melanoma includes wild type BRAF).In some embodiments, melanoma includes wild type BRAF. In some embodiments, melanoma includes BRAF mutant, and such as activity increases (for example, kinase activity increases and/or and wild type BRAF compared to activity increase) BRAF mutant or the enhanced mutant of BRAF functions.In some embodiments, melanoma packet Include BRAF constitutive activity mutant.In some embodiments, mutant BRAF has raised activity, such as raised kinases Activity.In some embodiments, mutant BRAF is the enhanced mutant of function.In some embodiments, BRAF's is prominent Become in kinase domain.In some embodiments, melanoma includes one or more in following BRAF mutation：R461I、 I462S、G463E、G463V、G465A、G465E、G465V、G468A、G468E、N580S、E585K、D593V、F594L、 G595R, L596V, T598I, V599D, V599E, V599K, V599R, K600E or A727V.In some embodiments, melanocyte Tumor includes BRAF V600E mutation.The mutation (one or more) of BRAF is identified using methods known in the art.
For example, the method that the melanoma (for example, metastatic cutaneous melanoma) for the treatment of individual (for example, people) is provided, including The composition that individual includes the nano particle containing taxane (for example, taxol) and carrier protein (for example, albumin) is given, Wherein melanoma does not include BRAF mutant, and such as activity increases (for example, kinase activity increases and/or compared with wild type BRAF Activity increase) BRAF mutant or the enhanced mutant of BRAF functions.In some embodiments, provide treatment individual (example Such as, people) melanoma (for example, metastatic cutaneous melanoma) method, including give individual include containing taxane (for example, Taxol) and carrier protein (for example, albumin) nano particle composition, wherein melanoma does not include BRAF V600E prominent Become (for example, melanoma includes wild type BRAF).In some embodiments, the melanoma for the treatment of individual (for example, people) is provided The method of (for example, metastatic cutaneous melanoma), including it includes containing taxane (for example, taxol) and carrier egg to give individual The composition of the nano particle of (for example, albumin) in vain, wherein melanoma include wild type BRAF.In some embodiments, The method that the melanoma (for example, metastatic cutaneous melanoma) for the treatment of individual (for example, people) is provided, including it includes containing to give individual There are the composition of the nano particle of taxane (for example, taxol) and carrier protein (for example, albumin), wherein melanoma to include The BRAF that BRAF mutant, such as activity increase (for example, kinase activity increases and/or activity increases compared with wild type BRAF) is prominent Variant or the enhanced mutant of BRAF functions.In some embodiments, the melanoma (example for the treatment of individual (for example, people) is provided Such as, metastatic cutaneous melanoma) method, including give individual include contain taxane (for example, taxol) and carrier protein The composition of the nano particle of (for example, albumin), wherein melanoma include BRAF V600E mutation.In some embodiments In, individual has IV stages or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma).In some embodiments In, melanoma is metastatic malignant melanoma.In some embodiments, metastatic melanoma the M1a stages, the M1b stages or The M1c stages.In some embodiments, metastatic melanoma is in the M1c stages.In some embodiments, individual, which has, increases Serum LDH it is horizontal.In some embodiments, individual has about any of following Serum LDH：<0.8×ULN、 0.4-0.8×ULN、0.8-1.1×ULN、0.9-1.1×ULN、0.8-1.2×ULN、1.1-1.5×ULN、1.2-1.5× ULN, 1.1-2 × ULN or 1.5-2 × ULN.In some embodiments, individual has the Serum LDH less than about 0.8 × ULN. In some embodiments, individual have about 0.8 × to the Serum LDH of about 1.1 × ULN.In some embodiments, individual tool Have greater than about 1.1 × to the Serum LDH between about 2.0 × ULN.In some embodiments, individual have about 1.1 × to about Serum LDH between 2.0 × ULN.In some embodiments, individual is people's (for example, sex).In some embodiment party In formula, taxane is taxol.In some embodiments, carrier protein is albumin.In some embodiments, purple is utilized The method of China fir alkane nano particle treatment melanoma is used as monotherapy.In some embodiments, taxane nanometer is utilized The method of granule therapy melanoma does not further comprise other therapeutic agents (such as other chemotherapeutics or immunotherapeutic agent).In some realities It applies in mode, method does not further comprise cytotoxic chemotherapeutic agent.
In some embodiments of any method described herein, melanoma includes the mutation of BRAF.In some embodiment party In formula, melanoma includes V600E BRAF mutation.In some embodiments, melanoma does not include mutation or the BRAF of BRAF Mutation feminine gender.In some embodiments, melanoma includes wild type BRAF.In some implementations of any method described herein In mode, melanoma includes the mutation of viral (v-ras) the oncogene homologues (" NRAS ") of neuroblastoma RAS.One In a little embodiments, melanoma does not include mutation or the NRAS mutation feminine gender of NRAS.In some embodiments, melanoma Including wild type NRAS.In some embodiments of any method described herein, melanoma includes phosphatase and tensin The mutation of homologue (" PTEN ").In some embodiments, melanoma does not include mutation or the PTEN mutation feminine gender of PTEN 's.In some embodiments, melanoma includes wild type PTEN.In some embodiments, melanoma includes (i) wild type The mutation of BRAF or BRAF；(ii) mutation of wild type NRAS or NRAS；And/or the mutation of (iii) wild type PTEN or PTEN. In some embodiments, melanoma is three negative melanomas, or including wild type BRAF, wild type NRAS and wild type PTEN.Determine that melanoma or individual with melanoma include gene or proteins wild type using methods known in the art Or gene or protein mutant (one or more) as described herein.
Individual described herein is people in some embodiments.In some embodiments, individual is male.In some realities It applies in mode, individual is women.In some embodiments, individual be at least about 25,30,35,40,45,50,55,60,65, 70,75,80,85 or any of 90 years old.In some embodiments, individual about 25,30,35,40,45,50,55,60, 65,70,75,80,85 or any of 90 years old it is following.In some embodiments, individual be about 25,30,35,40,45,50, 55,60,65,70,75,80,85 or any of 90 years old.In some embodiments, individual was at about 65 years old or less.In some realities It applies in mode, individual is at least about 65 years old (for example, any of at least about 70,75 or 80 years old).In some embodiments, Single lesion is presented in individual.In some embodiments, multiple lesions are presented in individual.The individual that can be treated with methods described herein Any one of can be following：White man's race or race, Asia race or race, Africa or Africa or U.S.'s race or race, Spain's race or race, Latin race or race or Hawaii or Pacific Ocean islander's race or race.
In some embodiments, individual is to present and suffer from melanoma (for example, IV stages or metastatic melanoma) phase The people for the one or more symptoms closed.In some embodiments, individual is easy to (for example, having in terms of heredity or other Risk factors) generate melanoma.These risk factors include but not limited to, the age, sex, race, diet, medical history before, Life style or custom, gene (for example, heredity) factor and environmental exposure (being such as exposed to sunlight).In some embodiments, Individual is that SPARC expression is positive (for example, being based on IHC standards).In some embodiments, individual is that SPARC expression is negative 's.
Method provided herein can be put into practice under secondary setup (setting).Secondary setup can be referred to such clinic and set It is fixed：Medical history of the individual with cancer as described herein, and usually (but not necessarily) in response to therapy --- include but not limited to, Operation (for example, operation excision), radiotherapy and chemotherapy；However, due to its cancer medical history, these individuals are considered having production The risk of the raw disease.Treatment under secondary setup is given and refers to later therapeutic modality.Degree of risk is (for example, assisting When the lower individual of setting is considered having " high risk " or " low-risk ") depend on a number of factors, most commonly be to treat first time When disease degree.
In some embodiments, this method is put into practice under new secondary setup, that is, method can be in original/determining therapy Preceding progress.In some embodiments, this method is used to before treating receive the individual for the treatment of.It is provided herein any to control Treatment method can be used for not receiving before treating the individual for the treatment of.
Method described herein can be used for receiving before treating the individual with melanoma of the treatment for melanoma. It may include chemotherapeutant such as Dacarbazine or DTIC (also referred to as DIC, DTIC-Dome or imidazole carboxamide) in preceding treatment. In some embodiments, include that (or Genasense is purchased from Genta to oblimersen (Oblimersen) in preceding treatment Inc.).In some embodiments, include immunotherapy (such as proleulzin (IL-2) or interferon (IFN)) in preceding treatment. Include BRAF inhibitor in preceding treatment in some embodiments, as (or Zelboraf is purchased from Genentech to the non-Buddhist nun of Wella USA, Inc.), GDC-0879 (being purchased from Tocris Bioscience), PLX-4720 (being purchased from Symansis), darafinib (Dabrafenib) (or GSK2118436), LGX 818, CEP-32496, UI-152, RAF 265, Rui Gefeini (Regorafenib) (BAY 73-4506), CCT239065 or Sorafenib (Sorafenib) (or Sorafenib Tosylate OrIt is purchased from Bayer Pharmaceuticals Corp.).In some embodiments, include in preceding treatment Her wooden monoclonal antibody (or MDX-010, MDX-101 or Yervoy, be purchased from Bristol-Myers Squibb).In some embodiment party In formula, received the treatment for melanoma before individual, and individual is substantially refractory in preceding treatment.In some implementations In mode, received the treatment for melanoma before individual, and was no longer respond to or only part is in response in preceding treatment. In some embodiments, individual initial response is in progress on the basis of preceding treatment in preceding treatment.In some embodiments In, individual is not responsive in preceding treatment.
Method described herein can be used as the use of the first gamma therapy.Method described herein can also be controlled in preceding melanoma It treats no longer valid or is substantially used as the second line or third gamma therapy after failure or the substantially refractory melanoma of the first gamma therapy It uses.In some embodiments, melanoma is that the first gamma therapy of BRAF inhibitor is substantially refractory.In some embodiments In, the therapy (for example, chemotherapy or immunotherapy) that individual had received an at least line before receiving treatment described herein is come Treat melanoma (for example, IV stages or metastatic melanoma).In some embodiments, patient has received the therapy or 2 of 1 line The therapy (for example, the chemotherapy or immunotherapy of 1 line or chemotherapy or immunotherapy of 2 lines) of line.Therefore, described herein Treatment can be used as the second gamma therapy or third gamma therapy.The therapy in front as described herein can be front chemotherapy or Immunotherapy.The therapy of First Line may include any one of following：Dacarbazine or DTIC (also referred to as DIC, DTIC- Dome or imidazole carboxamide), oblimersen (or Genasense), immunotherapy (such as proleulzin (IL-2) or interferon (IFN), (the non-Buddhist nun of such as Wella (or Zelboraf), (being purchased from Symansis), reaches GDC-0879, PLX-4720 BRAF inhibitor La Feini (or GSK2118436), LGX 818, CEP-32496, UI-152, RAF 265, Rui Gefeini (BAY 73-4506), CCT239065 or Sorafenib (or Sorafenib Tosylate or)) or her wooden monoclonal antibody (or MDX-010, MDX-101 or Yervoy).
In some embodiments, the method that treatment autologous melanoma (for example, metastatic cutaneous melanoma) is provided, including Give individual effective dose includes the nano particle containing taxane (for example, taxol) and carrier protein (for example, albumin) Composition, wherein method uses as the second line or third gamma therapy.In some embodiments, provide treatment individual melanocyte The method of tumor, including give individual effective dose includes containing taxane (for example, taxol) and carrier protein (for example, white egg The composition of nano particle in vain), wherein method use under secondary setup.In some embodiments, treatment individual is provided The method of melanoma, including give individual effective dose include containing taxane (for example, taxol) and carrier protein (for example, Albumin) nano particle composition, wherein method uses under new secondary setup.In some embodiments, individual tool There are IV stages or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma).In some embodiments, melanoma It is metastatic malignant melanoma.In some embodiments, metastatic melanoma is in M1a stages, M1b stages or M1c stages. In some embodiments, metastatic melanoma is in the M1c stages.In some embodiments, melanoma includes the mutation of BRAF. In some embodiments, melanoma does not include the mutation of BRAF.In some embodiments, melanoma does not include that BRAF is mutated Body, such as activity increase (for example, kinase activity increase and/or with wild type BRAF compared with activity increase) BRAF mutant or The enhanced mutant of BRAF functions.In some embodiments, melanoma does not include BRAF V600E mutation (for example, melanoma Including wild type BRAF).In some embodiments, melanoma includes wild type BRAF.In some embodiments, melanoma Including BRAF mutant, as activity increases (for example, kinase activity increases and/or activity increases compared with wild type BRAF) BRAF mutant or the enhanced mutant of BRAF functions.In some embodiments, melanoma includes BRAF V600E mutation. In some embodiments, individual has raised Serum LDH horizontal.In some embodiments, individual has about following any The Serum LDH of kind：<0.8×ULN、0.4-0.8×ULN、0.8-1.1×ULN、0.9-1.1×ULN、0.8-1.2×ULN、 1.1-1.5 × ULN, 1.2-1.5 × ULN, 1.1-2 × ULN or 1.5-2 × ULN.In some embodiments, individual has small In the Serum LDH of about 0.8 × ULN.In some embodiments, individual have about 0.8 × to the Serum LDH of about 1.1 × ULN. In some embodiments, individual have greater than about 1.1 × to the Serum LDH between about 2.0 × ULN.In some embodiments In, individual has about 1.1 × to the Serum LDH between about 2.0 × ULN.In some embodiments, individual is people (for example, man Property or women).In some embodiments, taxane is taxol.In some embodiments, carrier protein is albumin. In some embodiments, it is used as monotherapy using the method that taxane nano particle treats melanoma.In some realities It applies in mode, does not further comprise other therapeutic agents (such as other chemotherapy using the method that taxane nano particle treats melanoma Agent or immunotherapeutic agent).In some embodiments, method does not further comprise cytotoxic chemotherapeutic agent.
In some embodiments, the IV stages for treating individual (for example, people) or metastatic melanoma are provided (for example, IV Stage or metastatic cutaneous melanoma) method, including give individual include contain taxane (for example, taxol) and carrier egg The composition of the nano particle of (for example, albumin) in vain, wherein melanoma include BRAF mutant, such as activity increase (for example, Kinase activity increase and/or with wild type BRAF compared with activity increase) BRAF mutant or the enhanced mutant of BRAF functions. In some embodiments, provide treatment individual (for example, people) the IV stages or metastatic melanoma (for example, the IV stages or turning Shifting property cutaneous melanoma) method, including give individual include containing taxane (for example, taxol) and carrier protein (for example, Albumin) nano particle composition, wherein melanoma includes wild type BRAF.In some embodiments, treatment is provided The method in the IV stages or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma) of individual (for example, people), including The composition that individual includes the nano particle containing taxane (for example, taxol) and carrier protein (for example, albumin) is given, Wherein melanoma includes BRAF mutant, and such as activity increases (for example, kinase activity increases and/or lives compared with wild type BRAF Property increase) BRAF mutant or the enhanced mutant of BRAF functions.In some embodiments, provide treatment individual (for example, People) the IV stages or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma) method, including give individual packet Include the composition of the nano particle containing taxane (for example, taxol) and carrier protein (for example, albumin), wherein melanoma It is mutated including BRAF V600E.In some embodiments, the taxane in nano particle is coated with carrier protein.In some realities It applies in mode, the average or mean value grain size of nano particle is not greater than about 200nm (such as less than about 200nm) in composition.At some In embodiment, taxane is taxol.In some embodiments, carrier protein is albumin, such as human serum albumins or Human albumin.
In some embodiments, the IV stages for treating individual (for example, people) or metastatic melanoma are provided (for example, IV Stage or metastatic cutaneous melanoma) method, including it includes the nano particle containing taxol and albumin to give individual Composition, wherein melanoma include wild type BRAF.In some embodiments, the IV ranks for the treatment of individual (for example, people) are provided The method of section or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma), including it includes containing purple to give individual The composition of the nano particle of China fir alcohol and albumin, wherein melanoma include wild type BRAF, wherein the Japanese yew in nano particle Alcohol is coated with albumin.In some embodiments, IV stages or the metastatic melanoma for the treatment of individual (for example, people) are provided The method of (for example, IV stages or metastatic cutaneous melanoma), including it includes receiving containing taxol and albumin to give individual The composition of rice grain, wherein melanoma include wild type BRAF, and the wherein taxol in nano particle is coated with albumin, The average or mean value grain size of nano particle is not greater than about 200nm (such as less than about 200nm) in middle composition.In some embodiments In, albumin is human albumin.In some embodiments, albumin is human serum albumins.In some embodiments, in vain Albumen is recombinant albumin.In some embodiments, the method for melanoma is treated as single using taxane nano particle Therapy uses.In some embodiments, do not further comprise other using the method that taxane nano particle treats melanoma Therapeutic agent (such as other chemotherapeutics or immunotherapeutic agent).In some embodiments, method does not further comprise cytotoxicity Treat agent.
In some embodiments, the IV stages for treating individual (for example, people) or metastatic melanoma are provided (for example, IV Stage or metastatic cutaneous melanoma) method, including it includes the nano particle containing taxol and albumin to give individual Composition, wherein melanoma include BRAF mutation, as BRAF V600E are mutated.In some embodiments, treatment individual is provided The method of the IV stages of (for example, people) or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma), including give Individual includes the composition of the nano particle containing taxol and albumin, and wherein melanoma includes BRAF mutation, such as BRAF V600E is mutated, and wherein the taxol in nano particle is coated with albumin.In some embodiments, provide treatment individual (example Such as, people) the IV stages or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma) method, including give Body includes the composition of the nano particle containing taxol and albumin, and wherein melanoma includes BRAF mutation, such as BRAF V600E is mutated, and wherein the taxol in nano particle is coated with albumin, the average or mean value of nano particle wherein in composition Grain size is not greater than about 200nm (such as less than about 200nm).In some embodiments, albumin is human albumin.In some implementations In mode, albumin is human serum albumins.In some embodiments, albumin is recombinant albumin.In some embodiment party In formula, used as monotherapy using the method that taxane nano particle treats melanoma.In some embodiments, it utilizes The method of taxane nano particle treatment melanoma does not further comprise other therapeutic agents (such as other chemotherapeutics or immunization therapy Agent).In some embodiments, method does not further comprise cytotoxic chemotherapeutic agent.
In some embodiments, IV stages or the metastatic in the metastatic M1c stages for the treatment of individual (for example, people) are provided The method of melanoma (for example, IV stages or metastatic cutaneous melanoma), including give individual include containing taxane (for example, Taxol) and carrier protein (for example, albumin) nano particle composition, wherein melanoma include BRAF mutant, As activity increases the BRAF mutant or BRAF of (for example, kinase activity increases and/or activity increases compared with wild type BRAF) The enhanced mutant of function.In some embodiments, the IV ranks in the metastatic M1c stages for the treatment of individual (for example, people) are provided The method of section or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma), including it includes containing purple to give individual The composition of the nano particle of China fir alkane (for example, taxol) and carrier protein (for example, albumin), wherein melanoma includes wild Type BRAF.In some embodiments, IV stages or the metastatic in the metastatic M1c stages for the treatment of individual (for example, people) are provided The method of melanoma (for example, IV stages or metastatic cutaneous melanoma), including give individual include containing taxane (for example, Taxol) and carrier protein (for example, albumin) nano particle composition, wherein melanoma includes BRAF mutant, such as Activity increases the BRAF mutant or BRAF work(of (for example, kinase activity increases and/or activity increases compared with wild type BRAF) It can enhanced mutant.In some embodiments, the IV stages in the metastatic M1c stages for the treatment of individual (for example, people) are provided Or the method for metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma), including it includes containing Japanese yew to give individual The composition of the nano particle of alkane (for example, taxol) and carrier protein (for example, albumin), wherein melanoma includes BRAF V600E is mutated.In some embodiments, the taxane in nano particle is coated with carrier protein.In some embodiments, The average or mean value grain size of nano particle is not greater than about 200nm (such as less than about 200nm) in composition.In some embodiments In, taxane is taxol.In some embodiments, carrier protein is albumin, such as human serum albumins or human albumin. In some embodiments, IV stages or the metastatic melanoma in the metastatic M1c stages for the treatment of individual (for example, people) are provided The method of (for example, IV stages or metastatic cutaneous melanoma), including it includes receiving containing taxol and albumin to give individual The composition of rice grain, wherein melanoma include wild type BRAF.In some embodiments, provide treatment individual (for example, People) the metastatic M1c stages the IV stages or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma) side Method, including the composition that individual includes the nano particle containing taxol and albumin is given, wherein melanoma includes wild type BRAF, the wherein taxol in nano particle are coated with albumin.In some embodiments, provide treatment individual (for example, People) the metastatic M1c stages the IV stages or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma) side Method, including the composition that individual includes the nano particle containing taxol and albumin is given, wherein melanoma includes wild type BRAF, the wherein taxol in nano particle are coated with albumin, the average or mean value grain size of nano particle wherein in composition No more than about 200nm (such as less than about 200nm).In some embodiments, the metastatic for the treatment of individual (for example, people) is provided The method of the IV stages in M1c stages or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma), including give a Body includes the composition of the nano particle containing taxol and albumin, and wherein melanoma includes BRAF mutation, such as BRAF V600E is mutated.In some embodiments, IV stages or the transfer in the metastatic M1c stages for the treatment of individual (for example, people) are provided Property melanoma (for example, IV stages or metastatic cutaneous melanoma) method, including it includes containing taxol and white to give individual The composition of the nano particle of albumen, wherein melanoma include BRAF mutation, if BRAF V600E are mutated, wherein in nano particle Taxol be coated with albumin.In some embodiments, the metastatic M1c stages for the treatment of individual (for example, people) are provided The method of IV stages or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma), including it includes containing to give individual There is the composition of the nano particle of taxol and albumin, wherein melanoma includes BRAF mutation, if BRAF V600E are mutated, Taxol in middle nano particle is coated with albumin, and the average or mean value grain size of nano particle is not greater than about wherein in composition 200nm (such as less than about 200nm).In some embodiments, albumin is human albumin.In some embodiments, white egg It is human serum albumins in vain.In some embodiments, albumin is recombinant albumin.In some embodiments, purple is utilized The method of China fir alkane nano particle treatment melanoma is used as monotherapy.In some embodiments, taxane nanometer is utilized The method of granule therapy melanoma does not further comprise other therapeutic agents (such as other chemotherapeutics or immunotherapeutic agent).In some realities It applies in mode, method does not further comprise cytotoxic chemotherapeutic agent.
In some embodiments, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, including give Individual a) a effective amount of includes the composition of the nano particle containing taxol and albumin, wherein receiving utilization before individual The treatment for melanoma of at least one BRAF inhibitor (e.g., for example, the non-Buddhist nun of Wella (Zelboraf) or Sorafenib). In some embodiments, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, including give individual a) effective What is measured includes the composition of the nano particle containing taxol and albumin, and wherein the dosage of Nanoparticulate compositions is about 50mg/m2To about 200mg/m2Between (e.g., for example, about 100mg/m2To about 150mg/m2, for example, about 100mg/m2), wherein a Received the needle using at least one BRAF inhibitor (e.g., for example, the non-Buddhist nun of Wella (Zelboraf) or Sorafenib) before body Treatment to melanoma, and wherein individual is substantially refractory in preceding BRAF inhibitor for treating.In some embodiments, The method that treatment individual human melanoma (such as metastatic melanoma) is provided, including it includes containing Japanese yew to give individual a) a effective amount of The dosage of the composition of the nano particle of alcohol and albumin, wherein Nanoparticulate compositions is about 100mg/m2, wherein individual Before received using at least one BRAF inhibitor (e.g., for example, the non-Buddhist nun of Wella (Zelboraf) or Sorafenib) be directed to it is black The treatment of plain tumor, and wherein individual is substantially refractory in preceding BRAF inhibitor for treating.
In some embodiments, the IV stages for treating individual (for example, people) or metastatic melanoma are provided (for example, IV Stage or metastatic cutaneous melanoma) method, including give individual include contain taxane (for example, taxol) and carrier egg The composition of the nano particle of (for example, albumin) in vain, wherein melanoma include BRAF mutant, such as activity increase (for example, Kinase activity increase and/or with wild type BRAF compared with activity increase) BRAF mutant or the enhanced mutant of BRAF functions, Wherein individual has following any Serum LDH：Less than about 0.8 × ULN, about 0.8 × to about 1.1 × ULN, greater than about 1.1 × To between about 2.0 × ULN or about 1.1 × between about 2.0 × ULN.In some embodiments, provide treatment individual (for example, People) the IV stages or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma) method, including give individual packet Include the composition of the nano particle containing taxane (for example, taxol) and carrier protein (for example, albumin), wherein melanoma Including wild type BRAF, wherein individual has following any Serum LDH：Less than about 0.8 × ULN, about 0.8 × to about 1.1 × ULN, greater than about 1.1 × between about 2.0 × ULN or about 1.1 × between about 2.0 × ULN.In some embodiments, it carries For the treatment individual IV stages of (for example, people) or the side of metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma) Method, including it includes the nano particle containing taxane (for example, taxol) and carrier protein (for example, albumin) to give individual Composition, wherein melanoma include BRAF mutant, such as activity increase (for example, kinase activity increase and/or with wild type BRAF Compared to activity increase) BRAF mutant or the enhanced mutant of BRAF functions, wherein individual have following any serum LDH：Less than about 0.8 × ULN, about 0.8 × to about 1.1 × ULN, greater than about 1.1 × between about 2.0 × ULN or about 1.1 × extremely Between about 2.0 × ULN.In some embodiments, IV stages or the metastatic melanoma for the treatment of individual (for example, people) are provided The method of (for example, IV stages or metastatic cutaneous melanoma), including it includes containing taxane (for example, taxol) to give individual With the composition of the nano particle of carrier protein (for example, albumin), wherein melanoma includes BRAF V600E mutation, wherein a Body has following any Serum LDH：Less than about 0.8 × ULN, about 0.8 × to about 1.1 × ULN, greater than about 1.1 × to about 2.0 Between × ULN or about 1.1 × between about 2.0 × ULN.
In some embodiments, the IV stages for treating individual (for example, people) or metastatic melanoma are provided (for example, IV Stage or metastatic cutaneous melanoma) method, including give individual include contain taxane (for example, taxol) and carrier egg The composition of the nano particle of (for example, albumin) in vain, wherein melanoma include wild type BRAF, are less than about wherein individual has The Serum LDH of 0.8 × ULN.In some embodiments, IV stages or the metastatic melanocyte for the treatment of individual (for example, people) are provided The method of tumor (for example, IV stages or metastatic cutaneous melanoma), including it includes containing taxane (for example, Japanese yew to give individual Alcohol) and carrier protein (for example, albumin) nano particle composition, wherein melanoma includes wild type BRAF, wherein a Body has about 0.8 × to the Serum LDH of about 1.1 × ULN.In some embodiments, the IV for the treatment of individual (for example, people) is provided The method of stage or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma), including it includes containing to give individual The composition of the nano particle of taxane (for example, taxol) and carrier protein (for example, albumin), wherein melanoma include open country Raw type BRAF, wherein individual have greater than about 1.1 × between about 2.0 × ULN or about 1.1 × to the blood between about 2.0 × ULN Clear LDH.In some embodiments, the taxane in nano particle is coated with carrier protein.In some embodiments, it combines The average or mean value grain size of nano particle is not greater than about 200nm (such as less than about 200nm) in object.In some embodiments, purple China fir alkane is taxol.In some embodiments, carrier protein is albumin, such as human serum albumins or human albumin.One In a little embodiments, the IV stages for treating individual (for example, people) or metastatic melanoma are provided (for example, IV stages or metastatic Cutaneous melanoma) method, including the composition that individual includes the nano particle containing taxol and albumin is given, wherein black Plain tumor includes wild type BRAF, wherein individual has following any Serum LDH：Less than about 0.8 × ULN, about 0.8 × to about 1.1 × ULN, greater than about 1.1 × between about 2.0 × ULN or about 1.1 × between about 2.0 × ULN.
In some embodiments, the IV stages for treating individual (for example, people) or metastatic melanoma are provided (for example, IV Stage or metastatic cutaneous melanoma) method, including it includes the nano particle containing taxol and albumin to give individual Composition, wherein melanoma include wild type BRAF, and the wherein taxol in nano particle is coated with albumin, wherein individual tool There is following any Serum LDH：Less than about 0.8 × ULN, about 0.8 × to about 1.1 × ULN, greater than about 1.1 × to about 2.0 × Between ULN or about 1.1 × between about 2.0 × ULN.In some embodiments, the IV ranks for the treatment of individual (for example, people) are provided The method of section or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma), including it includes containing purple to give individual The composition of the nano particle of China fir alcohol and albumin, wherein melanoma include wild type BRAF, wherein the Japanese yew in nano particle Alcohol is coated with albumin, and the average or mean value grain size of nano particle is not greater than about 200nm (such as less than about wherein in composition 200nm), wherein individual has following any Serum LDH：Less than about 0.8 × ULN, about 0.8 × to about 1.1 × ULN, be more than About 1.1 × between about 2.0 × ULN or about 1.1 × between about 2.0 × ULN.In some embodiments, treatment is provided The method of the IV stages of body (for example, people) or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma), including give The composition that individual includes the nano particle containing taxol and albumin is given, wherein melanoma includes BRAF mutation, such as BRAF V600E is mutated, wherein individual has following any Serum LDH：Less than about 0.8 × ULN, about 0.8 × to about 1.1 × ULN, big In about 1.1 × between about 2.0 × ULN or about 1.1 × between about 2.0 × ULN.In some embodiments, treatment is provided The method in the IV stages or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma) of individual (for example, people), including The composition that individual includes the nano particle containing taxol and albumin is given, wherein melanoma includes BRAF mutation, such as BRAF V600E mutation, wherein the taxol in nano particle is coated with albumin, wherein individual has following any serum LDH：Less than about 0.8 × ULN, about 0.8 × to about 1.1 × ULN, greater than about 1.1 × between about 2.0 × ULN or about 1.1 × extremely Between about 2.0 × ULN.
In some embodiments, the IV stages for treating individual (for example, people) or metastatic melanoma are provided (for example, IV Stage or metastatic cutaneous melanoma) method, including it includes the nano particle containing taxol and albumin to give individual Composition, wherein melanoma include BRAF mutation, and if BRAF V600E are mutated, wherein the taxol in nano particle is coated with white Albumen, the average or mean value grain size of nano particle is not greater than about 200nm (such as less than about 200nm) wherein in composition, wherein a Body has following any Serum LDH：Less than about 0.8 × ULN, about 0.8 × to about 1.1 × ULN, greater than about 1.1 × to about 2.0 Between × ULN or about 1.1 × between about 2.0 × ULN.In some embodiments, individual has less than about 0.8 × ULN's Serum LDH.In some embodiments, individual, which has, is less than about 0.8 × ULN about 0.8 × to the Serum LDH of about 1.1 × ULN. In some embodiments, individual have greater than about 1.1 × between about 2.0 × ULN or about 1.1 × between about 2.0 × ULN Serum LDH.In some embodiments, albumin is human albumin.In some embodiments, albumin is human seralbumin Albumen.In some embodiments, albumin is recombinant albumin.In some embodiments, taxane nano particle is utilized The method for the treatment of melanoma is used as monotherapy.In some embodiments, melanocyte is treated using taxane nano particle The method of tumor does not further comprise other therapeutic agents (such as other chemotherapeutics or immunotherapeutic agent).In some embodiments, side Method does not further comprise cytotoxic chemotherapeutic agent.
In some embodiments, the IV stages for treating individual (for example, people) or metastatic melanoma are provided (for example, IV Stage or metastatic cutaneous melanoma) method, including give individual include contain taxane (for example, taxol) and carrier egg The composition of the nano particle of (for example, albumin) in vain, wherein individual has following any Serum LDH：Less than about 0.8 × ULN, about 0.8 × to about 1.1 × ULN, greater than about 1.1 × between about 2.0 × ULN or about 1.1 × between about 2.0 × ULN. In some embodiments, provide treatment individual (for example, people) the IV stages or metastatic melanoma (for example, the IV stages or turning Shifting property cutaneous melanoma) method, including give individual include containing taxane (for example, taxol) and carrier protein (for example, Albumin) nano particle composition, wherein individual have less than about 0.8 × ULN Serum LDH.In some embodiments In, IV stages or the metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma) for the treatment of individual (for example, people) are provided Method, including it includes the nanometer containing taxane (for example, taxol) and carrier protein (for example, albumin) to give individual The composition of grain, wherein individual have about 0.8 × to the Serum LDH of about 1.1 × ULN.In some embodiments, treatment is provided The method in the IV stages or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma) of individual (for example, people), including The composition that individual includes the nano particle containing taxane (for example, taxol) and carrier protein (for example, albumin) is given, Wherein individual have greater than about 1.1 × between about 2.0 × ULN or about 1.1 × to the Serum LDH between about 2.0 × ULN. In some embodiments, the taxane in nano particle is coated with carrier protein.In some embodiments, nanometer in composition The average or mean value grain size of particle is not greater than about 200nm (such as less than about 200nm).In some embodiments, taxane is purple China fir alcohol.In some embodiments, carrier protein is albumin, such as human serum albumins or human albumin.In some embodiment party In formula, the IV stages for treating individual (for example, people) or metastatic melanoma are provided (for example, IV stages or metastatic the black pigment of skin Tumor) method, including the composition that individual includes the nano particle containing taxol and albumin is given, under wherein individual has Arrange any Serum LDH：Less than about 0.8 × ULN, about 0.8 × to about 1.1 × ULN, greater than about 1.1 × to about 2.0 × ULN it Between or about 1.1 × between about 2.0 × ULN.In some embodiments, provide treatment individual (for example, people) the IV stages or The method of metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma), including it includes containing taxol to give individual With the composition of the nano particle of albumin, wherein individual have following any Serum LDH：Less than about 0.8 × ULN, about 0.8 × to about 1.1 × ULN, greater than about 1.1 × between about 2.0 × ULN or about 1.1 × between about 2.0 × ULN, wherein nanometer Taxol in particle is coated with albumin.In some embodiments, the IV stages for the treatment of individual (for example, people) are provided or are turned The method of shifting property melanoma (for example, IV stages or metastatic cutaneous melanoma), including give individual include containing taxol and The composition of the nano particle of albumin, wherein individual has following any Serum LDH：Less than about 0.8 × ULN, about 0.8 × To about 1.1 × ULN, greater than about 1.1 × between about 2.0 × ULN or about 1.1 × between about 2.0 × ULN, wherein nanometer Taxol in grain is coated with albumin, and the average or mean value grain size of nano particle is not greater than about 200nm (such as wherein in composition Less than about 200nm).In some embodiments, individual has the Serum LDH less than about 0.8 × ULN.In some embodiments In, individual, which has, is less than about 0.8 × ULN about 0.8 × to the Serum LDH of about 1.1 × ULN.In some embodiments, individual tool Have greater than about 1.1 × between about 2.0 × ULN or about 1.1 × to the Serum LDH between about 2.0 × ULN.In some embodiment party In formula, albumin is human albumin.In some embodiments, albumin is human serum albumins.In some embodiments, Albumin is recombinant albumin.In some embodiments, the method for melanoma is treated as single using taxane nano particle One therapy uses.In some embodiments, do not further comprise it using the method that taxane nano particle treats melanoma His therapeutic agent (such as other chemotherapeutics or immunotherapeutic agent).In some embodiments, method does not further comprise cytotoxicity Chemotherapeutics.
In some embodiments, the IV stages for treating individual (for example, people) or metastatic melanoma are provided (for example, IV Stage or metastatic cutaneous melanoma) method, including give individual include contain taxane (for example, taxol) and carrier egg The composition of the nano particle of (for example, albumin) in vain, wherein melanoma include BRAF mutant, such as activity increase (for example, Kinase activity increase and/or with wild type BRAF compared with activity increase) BRAF mutant or the enhanced mutant of BRAF functions, Wherein individual is people (women or male).In some embodiments, IV stages or the transfer for the treatment of individual (for example, people) are provided Property melanoma (for example, IV stages or metastatic cutaneous melanoma) method, including give individual include contain taxane (example Such as, taxol) and carrier protein (for example, albumin) nano particle composition, wherein melanoma includes BRAFV600E prominent Become, wherein individual is people (women or male).
In some embodiments, the IV stages for treating individual (for example, people) or metastatic melanoma are provided (for example, IV Stage or metastatic cutaneous melanoma) method, including give individual include contain taxane (for example, taxol) and carrier egg The composition of the nano particle of (for example, albumin) in vain, wherein melanoma include wild type BRAF, and wherein individual is people (women Or male).In some embodiments, the IV stages for treating individual (for example, people) or metastatic melanoma are provided (for example, IV Stage or metastatic cutaneous melanoma) method, including give individual include contain taxane (for example, taxol) and carrier egg The composition of the nano particle of (for example, albumin) in vain, wherein melanoma include BRAF mutant, and such as activity increases (for example, swashing Enzymatic activity increase and/or with wild type BRAF compared with activity increase) BRAF mutant or the enhanced mutant of BRAF functions, Middle individual is people (women or male).In some embodiments, IV stages or the metastatic for the treatment of individual (for example, people) are provided The method of melanoma (for example, IV stages or metastatic cutaneous melanoma), including give individual include containing taxane (for example, Taxol) and carrier protein (for example, albumin) nano particle composition, wherein melanoma includes BRAF V600E prominent Become, wherein individual is people (women or male).In some embodiments, provide treatment individual (for example, people) the IV stages or The method of metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma), including it includes containing taxane to give individual The composition of the nano particle of (for example, taxol) and carrier protein (for example, albumin), wherein melanoma includes wild type BRAF, wherein individual are woman.In some embodiments, IV stages or the metastatic for providing treatment individual (for example, people) are black The method of plain tumor (for example, IV stages or metastatic cutaneous melanoma), including it includes containing taxane (for example, purple to give individual China fir alcohol) and carrier protein (for example, albumin) nano particle composition, wherein melanoma includes wild type BRAF, wherein Individual is man.In some embodiments, the taxane in nano particle is coated with carrier protein.In some embodiments In, the average or mean value grain size of nano particle is not greater than about 200nm (such as less than about 200nm) in composition.In some embodiment party In formula, taxane is taxol.In some embodiments, carrier protein is albumin, such as human serum albumins or the white egg of people In vain.In some embodiments, treatment individual IV stages or metastatic melanoma are provided (for example, IV stages or metastatic skin Melanoma) method, including give the composition that individual includes the nano particle containing taxol and albumin, wherein melanoma Including wild type BRAF, wherein individual is people (women or male).In some embodiments, provide treatment the individual IV stages or The method of metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma), including it includes containing taxol to give individual With the composition of the nano particle of albumin, wherein melanoma includes wild type BRAF, the taxol packet wherein in nano particle There is albumin, wherein individual is people (women or male).In some embodiments, treatment individual IV stages or transfer are provided Property melanoma (for example, IV stages or metastatic cutaneous melanoma) method, including it includes containing taxol and white to give individual The composition of the nano particle of albumen, wherein melanoma include wild type BRAF, and the wherein taxol in nano particle is coated with Albumin, the average or mean value grain size of nano particle is not greater than about 200nm (such as less than about 200nm) wherein in composition, wherein Individual is people (women or male).In some embodiments, provide treatment the individual IV stages or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma) method, including it includes the nano particle containing taxol and albumin to give individual Composition, wherein melanoma include BRAF mutation, if BRAF V600E be mutated, wherein individual is people (women or male). In some embodiments, treatment individual IV stages or metastatic melanoma are provided (for example, IV stages or metastatic the black pigment of skin Tumor) method, including give the composition that individual includes the nano particle containing taxol and albumin, wherein melanoma includes BRAF is mutated, and if BRAF V600E are mutated, wherein the taxol in nano particle is coated with albumin, and wherein individual is people (female Property or male).In some embodiments, treatment individual IV stages or metastatic melanoma are provided (for example, IV stages or transfer Property cutaneous melanoma) method, including give the composition that individual includes the nano particle containing taxol and albumin, wherein Melanoma includes BRAF mutation, and if BRAF V600E are mutated, wherein the taxol in nano particle is coated with albumin, wherein group The average or mean value grain size for closing nano particle in object is not greater than about 200nm (such as less than about 200nm), and wherein individual is people (women Or male).In some embodiments, albumin is human albumin.In some embodiments, albumin is human seralbumin egg In vain.In some embodiments, albumin is recombinant albumin.In some embodiments, individual is man.In some implementations In mode, individual is woman.In some embodiments, the method for melanoma is treated as single using taxane nano particle Therapy uses.In some embodiments, do not further comprise other using the method that taxane nano particle treats melanoma Therapeutic agent (such as other chemotherapeutics or immunotherapeutic agent).In some embodiments, method does not further comprise cytotoxicity Treat agent.
In some embodiments, the IV stages for treating individual (for example, people) or metastatic melanoma are provided (for example, IV Stage or metastatic cutaneous melanoma) method, including give individual include contain taxane (for example, taxol) and carrier egg The composition of the nano particle of (for example, albumin) in vain, wherein melanoma include BRAF mutant, such as activity increase (for example, Kinase activity increase and/or with wild type BRAF compared with activity increase) BRAF mutant or the enhanced mutant of BRAF functions, Wherein individual is people (women or male), wherein individual about 65 years old or less or at least about 65 years old (for example, at least about 70,75 or Any of 80 years old).In some embodiments, IV stages or the metastatic melanoma for the treatment of individual (for example, people) are provided The method of (for example, IV stages or metastatic cutaneous melanoma), including it includes containing taxane (for example, taxol) to give individual With the composition of the nano particle of carrier protein (for example, albumin), wherein melanoma includes wild type BRAF, and wherein individual is People (women or male), wherein individual about 65 years old or less or at least about 65 years old (for example, at least about 70,75 or 80 years old times One).In some embodiments, the IV stages for treating individual (for example, people) or metastatic melanoma are provided (for example, IV ranks Section or metastatic cutaneous melanoma) method, including give individual include contain taxane (for example, taxol) and carrier protein The composition of the nano particle of (for example, albumin), wherein melanoma include BRAF mutant, and such as activity increases (for example, kinases Activity increase and/or with wild type BRAF compared with activity increase) BRAF mutant or the enhanced mutant of BRAF functions, wherein Individual is people (women or male), wherein individual at about 65 years old or less or at least about 65 years old (for example, at least about 70,75 or 80 years old Any of).In some embodiments, IV stages or the metastatic melanoma (example for the treatment of individual (for example, people) are provided Such as, IV stages or metastatic cutaneous melanoma) method, including give individual include containing taxane (for example, taxol) and The composition of the nano particle of carrier protein (for example, albumin), wherein melanoma include BRAF V600E mutation, wherein individual People (women or male), wherein individual at about 65 years old or less or at least about 65 years old (for example, at least about 70,75 or 80 years old Any one).In some embodiments, the IV stages for treating individual (for example, people) or metastatic melanoma are provided (for example, IV Stage or metastatic cutaneous melanoma) method, including give individual include contain taxane (for example, taxol) and carrier egg The composition of the nano particle of (for example, albumin) in vain, wherein melanoma include wild type BRAF, and wherein individual is people (women Or male), wherein individual was at about 65 years old or less.In some embodiments, provide treatment individual (for example, people) the IV stages or The method of metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma), including it includes containing taxane to give individual The composition of the nano particle of (for example, taxol) and carrier protein (for example, albumin), wherein melanoma includes wild type BRAF, wherein individual are people (women or males), wherein individual at least about 65 years old (for example, at least about 70,75 or 80 years old Any one).In some embodiments, the average or mean value grain size of nano particle is not greater than about 200nm (such as less than in composition About 200nm).In some embodiments, taxane is taxol.In some embodiments, carrier protein is albumin, such as Human serum albumins or human albumin.In some embodiments, made using the method that taxane nano particle treats melanoma It is used for monotherapy.In some embodiments, it is not wrapped further using the method that taxane nano particle treats melanoma Include other therapeutic agents (such as other chemotherapeutics or immunotherapeutic agent).In some embodiments, method does not further comprise cell Cytotoxic chemotherapeutic agent.
In some embodiments, the IV stages for treating individual (for example, people) or metastatic melanoma are provided (for example, IV Stage or metastatic cutaneous melanoma) method, including give individual include contain taxane (for example, taxol) and carrier egg The composition of the nano particle of (for example, albumin) in vain, wherein individual has following any Serum LDH：Less than about 0.8 × ULN, about 0.8 × to about 1.1 × ULN, greater than about 1.1 × between about 2.0 × ULN or about 1.1 × between about 2.0 × ULN, Wherein individual is people (women or male) (for example, at about 65 years old or less or at least about 65 years old).In some embodiments, it provides The method in the IV stages or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma) for the treatment of individual (for example, people), Including giving the group that individual includes the nano particle containing taxane (for example, taxol) and carrier protein (for example, albumin) Object is closed, wherein individual has the Serum LDH less than about 0.8 × ULN, wherein individual is people (women or male) (for example, about 65 Year old or less or at least about 65 years old).In some embodiments, IV stages or the metastatic for providing treatment individual (for example, people) are black The method of plain tumor (for example, IV stages or metastatic cutaneous melanoma), including it includes containing taxane (for example, purple to give individual China fir alcohol) and carrier protein (for example, albumin) nano particle composition, wherein individual have 0.8 × to about 1.1 × ULN Between Serum LDH, wherein individual is people (women or male) (for example, at about 65 years old or less or at least about 65 years old).At some In embodiment, the IV stages for treating individual (for example, people) or metastatic melanoma are provided (for example, IV stages or metastatic skin Skin melanoma) method, including it includes containing taxane (for example, taxol) and carrier protein (for example, white egg to give individual The composition of nano particle in vain), wherein individual have greater than about 1.1 × between about 2.0 × ULN or about 1.1 × to about 2.0 Serum LDH between × ULN, wherein individual are people (women or male) (for example, at about 65 years old or less or at least about 65 years old). In some embodiments, the taxane in nano particle is coated with carrier protein.In some embodiments, nanometer in composition The average or mean value grain size of particle is not greater than about 200nm (such as less than about 200nm).In some embodiments, taxane is purple China fir alcohol.In some embodiments, carrier protein is albumin, such as human serum albumins or human albumin.In some embodiment party In formula, used as monotherapy using the method that taxane nano particle treats melanoma.In some embodiments, it utilizes The method of taxane nano particle treatment melanoma does not further comprise other therapeutic agents (such as other chemotherapeutics or immunization therapy Agent).In some embodiments, method does not further comprise cytotoxic chemotherapeutic agent.
Method described herein can be used for the various aspects of melanoma therapy.In some embodiments, providing to utilize has Effect amount includes that the composition of the nano particle containing taxane and carrier protein treats the side of individual (for example, people) melanoma Method.In some embodiments, effective quantity is the amount for being enough to postpone melanoma generation.In some embodiments, effective quantity is It is enough to prevent or postpone melanoma generation and/or amount repeatedly.In some embodiments, effective quantity is included in through this paper institutes Any method for melanoma stated is enough to generate the amount of complete response when treating individual.In some embodiments, effectively Amount is enough to generate the amount of part response when being included in individual by any method treatment for melanoma as described herein.
In some embodiments, it is a effective amount of include containing taxane (for example, taxol) and carrier protein (for example, Albumin) nano particle composition cause complete response, part response, melanoma size reduction, transfer reduction, disease it is steady Fixed and/or Whole Response rate increases.In some embodiments, taxane is taxol.In some embodiments, carrier egg It is albumin in vain.Efficacy parameter (such as complete response or part respond) as described herein can be by well known by persons skilled in the art Any method determines.For example, efficacy parameter can be determined according to RECIST, such as RECIST versions 1.0 or 1.1 standards.RECIST editions This 1.1 standard is described in Eisenhauer EA et al.2009, Eur J Cancer., 45 (2):228-47, disclosed in Full content is incorporated by reference herein.
In some embodiments, the method for inhibiting individual Melanoma Cell Proliferation is provided, including gives individual effective dose Include the nano particle containing taxane (for example, taxol) and carrier protein (for example, albumin) composition.At some In embodiment, taxane is taxol.In some embodiments, carrier protein is albumin.In some embodiments, The method for inhibiting individual Melanoma Cell Proliferation is provided, including give individual effective dose includes containing taxol and albumin The composition of nano particle.In some embodiments, at least about 10% (including for example, at least about 20%, 30%, 40%, 60%, any in 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% It is a) cell Proliferation be suppressed.In some embodiments, individual have IV stages or metastatic melanoma (for example, the IV stages or Metastatic cutaneous melanoma).In some embodiments, melanoma is metastatic malignant melanoma.In some embodiments, Metastatic melanoma is in M1a stages, M1b stages or M1c stages.In some embodiments, metastatic melanoma is in M1c ranks Section.In some embodiments, melanoma includes the mutation of BRAF.Melanoma includes BRAF V600E in some embodiments Mutation.In some embodiments, melanoma does not include the mutation of BRAF.In some embodiments, melanoma does not include The BRAF that BRAF mutant, such as activity increase (for example, kinase activity increases and/or activity increases compared with wild type BRAF) is prominent Variant or the enhanced mutant of BRAF functions.In some embodiments, melanoma do not include BRAF V600E mutation (for example, Melanoma includes wild type BRAF).In some embodiments, melanoma includes wild type BRAF.In some embodiments, Melanoma includes BRAF mutant, and such as activity increases (for example, kinase activity increases and/or activity increases compared with wild type BRAF Add) BRAF mutant or the enhanced mutant of BRAF functions.In some embodiments, melanoma includes BRAF V600E prominent Become.In some embodiments, individual has raised Serum LDH horizontal.In some embodiments, individual has normal Serum LDH is horizontal.In some embodiments, individual has about following any Serum LDH：<0.8×ULN、0.4-0.8 ×ULN、0.8-1.1×ULN、0.9-1.1×ULN、0.8-1.2×ULN、1.1-1.5×ULN、1.2-1.5×ULN、1.1-2 × ULN or 1.5-2 × ULN.In some embodiments, individual has the Serum LDH less than about 0.8 × ULN.In some implementations In mode, individual has about 0.8 × to the Serum LDH of about 1.1 × ULN.In some embodiments, individual has greater than about 1.1 × to the Serum LDH between about 2.0 × ULN.In some embodiments, individual have about 1.1 × to about 2.0 × ULN it Between Serum LDH.In some embodiments, individual is people's (for example, sex).
In some embodiments, prevention is provided or inhibits a method for autologous melanoma transfer, including is given individual effective What is measured includes the composition of the nano particle containing taxane (for example, taxol) and carrier protein (for example, albumin).One In a little embodiments, taxane is taxol.In some embodiments, carrier protein is albumin.In some embodiments In, prevention is provided or inhibits a method for autologous melanoma transfer, including give individual effective dose includes containing taxol and white The composition of the nano particle of albumen.In some embodiments, at least about 10% (including for example, at least about 20%, 30%, 40%, any of 60%, 70%, 80%, 90%, 95% or 100%) transfer is suppressed.In some embodiments, it provides Postpone or slow down a method for autologous melanoma transfer, including give individual effective dose includes containing taxane and carrier protein The composition of the nano particle of (for example, albumin).In some embodiments, individual has IV stages or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma).In some embodiments, melanoma is metastatic malignant melanoma. In some embodiments, metastatic melanoma is in M1a stages, M1b stages or M1c stages.In some embodiments, metastatic Melanoma is in the M1c stages.In some embodiments, melanoma includes the mutation of BRAF.In some embodiments, melanoma It is mutated including BRAF V600E.In some embodiments, melanoma does not include the mutation of BRAF.In some embodiments, Including BRAF mutant, such as activity increases (for example, kinase activity increases and/or the activity compared with wild type BRAF melanoma Increase) BRAF mutant or the enhanced mutant of BRAF functions.In some embodiments, melanoma does not include BRAF V600E is mutated (for example, melanoma includes wild type BRAF).In some embodiments, melanoma includes wild type BRAF. In some embodiments, melanoma includes BRAF mutant, and such as activity increases (for example, kinase activity increases and/or and wild type BRAF compared to activity increase) BRAF mutant or the enhanced mutant of BRAF functions.In some embodiments, melanoma packet Include BRAF V600E mutation.In some embodiments, individual has raised Serum LDH horizontal.In some embodiments, Individual has normal Serum LDH horizontal.In some embodiments, individual has about following any Serum LDH：<0.8 ×ULN、0.4-0.8×ULN、0.8-1.1×ULN、0.9-1.1×ULN、0.8-1.2×ULN、1.1-1.5×ULN、1.2- 1.5 × ULN, 1.1-2 × ULN or 1.5-2 × ULN.In some embodiments, individual has the serum less than about 0.8 × ULN LDH.In some embodiments, individual have about 0.8 × to the Serum LDH of about 1.1 × ULN.In some embodiments, a Body has greater than about 1.1 × to the Serum LDH between about 2.0 × ULN.In some embodiments, individual have about 1.1 × extremely Serum LDH between about 2.0 × ULN.In some embodiments, individual is people's (for example, sex).
In some embodiments, the method for reducing an autologous melanoma size or reducing melanoma volume is provided, including is given Give individual effective dose includes the nano particle containing taxane (for example, taxol) and carrier protein (for example, albumin) Composition.In some embodiments, taxane is taxol.In some embodiments, carrier protein is albumin.One In a little embodiments, the method for reducing an autologous melanoma size or reducing melanoma volume is provided, including give individual effective dose Include the nano particle containing taxol and albumin composition.In some embodiments, tumor size or tumour body Product be reduced by least about 10% (including for example, at least about 20%, 30%, 40%, 60%, 70%, 80%, 90%, 95% or Any of 100%).In some embodiments, individual has IV stages or metastatic melanoma (for example, the IV stages or turning Shifting property cutaneous melanoma).In some embodiments, melanoma is metastatic malignant melanoma.In some embodiments, turn Shifting property melanoma is in M1a stages, M1b stages or M1c stages.In some embodiments, metastatic melanoma is in the M1c stages. In some embodiments, melanoma includes the mutation of BRAF.In some embodiments, melanoma includes BRAF V600E prominent Become.In some embodiments, melanoma does not include the mutation of BRAF.In some embodiments, melanoma does not include BRAF Mutant, such as activity increase the BRAF mutant of (for example, kinase activity increases and/or activity increases compared with wild type BRAF) Or the enhanced mutant of BRAF functions.In some embodiments, melanoma does not include BRAF V600E mutation (for example, melanocyte Tumor includes wild type BRAF).In some embodiments, melanoma includes wild type BRAF.In some embodiments, melanocyte Tumor includes BRAF mutant, as activity increases (for example, kinase activity increases and/or activity increases compared with wild type BRAF) BRAF mutant or the enhanced mutant of BRAF functions.In some embodiments, melanoma includes BRAF V600E mutation. In some embodiments, individual has raised Serum LDH horizontal.In some embodiments, individual has normal serum LDH is horizontal.In some embodiments, individual has about following any Serum LDH：<0.8×ULN、0.4-0.8× ULN、0.8-1.1×ULN、0.9-1.1×ULN、0.8-1.2×ULN、1.1-1.5×ULN、1.2-1.5×ULN、1.1-2× ULN or 1.5-2 × ULN.In some embodiments, individual has the Serum LDH less than about 0.8 × ULN.In some embodiment party In formula, individual has about 0.8 × to the Serum LDH of about 1.1 × ULN.In some embodiments, individual has greater than about 1.1 × to the Serum LDH between about 2.0 × ULN.In some embodiments, individual have about 1.1 × between about 2.0 × ULN Serum LDH.In some embodiments, individual is people's (for example, sex).
In some embodiments, it provides and extends a method for autologous melanoma disease developing time, including give individual to have Effect amount include the nano particle containing taxane (for example, taxol) and carrier protein (for example, albumin) composition. In some embodiments, taxane is taxol.In some embodiments, carrier protein is albumin.In some embodiment party It in formula, provides and extends a method for autologous melanoma disease developing time, including give individual effective dose includes containing taxol With the composition of the nano particle of albumin.In some embodiments, method make disease developing time extend at least about 1,2, 3, in 4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,2,24,26,28,30,35,40,45 or 50 weeks Any one.In some embodiments, individual has IV stages or metastatic melanoma (for example, IV stages or metastatic skin Melanoma).In some embodiments, melanoma is metastatic malignant melanoma.In some embodiments, metastatic melanocyte Tumor is in M1a stages, M1b stages or M1c stages.In some embodiments, metastatic melanoma is in the M1c stages.In some realities It applies in mode, melanoma includes the mutation of BRAF.In some embodiments, melanoma includes V600E BRAF mutation.One In a little embodiments, melanoma does not include the mutation of BRAF.In some embodiments, melanoma does not include BRAF mutant, As activity increases the BRAF mutant or BRAF of (for example, kinase activity increases and/or activity increases compared with wild type BRAF) The enhanced mutant of function.In some embodiments, melanoma does not include BRAF V600E mutation (for example, melanoma includes Wild type BRAF).In some embodiments, melanoma includes wild type BRAF.In some embodiments, melanoma includes The BRAF that BRAF mutant, such as activity increase (for example, kinase activity increases and/or activity increases compared with wild type BRAF) is prominent Variant or the enhanced mutant of BRAF functions.In some embodiments, melanoma includes BRAF V600E mutation.In some realities It applies in mode, individual has raised Serum LDH horizontal.In some embodiments, individual has normal Serum LDH water It is flat.In some embodiments, individual has about following any Serum LDH：<0.8×ULN、0.4-0.8×ULN、0.8- 1.1 × ULN, 0.9-1.1 × ULN, 0.8-1.2 × ULN, 1.1-1.5 × ULN, 1.2-1.5 × ULN, 1.1-2 × ULN or 1.5- 2×ULN.In some embodiments, individual has the Serum LDH less than about 0.8 × ULN.In some embodiments, individual With about 0.8 × to the Serum LDH of about 1.1 × ULN.In some embodiments, individual have greater than about 1.1 × to about 2.0 Serum LDH between × ULN.In some embodiments, individual have about 1.1 × to the Serum LDH between about 2.0 × ULN. In some embodiments, individual is people's (for example, sex).
In some embodiments, the method that the life cycle for extending the individual with melanoma is provided, including give individual A effective amount of includes the composition of the nano particle containing taxane (for example, taxol) and carrier protein (for example, albumin). In some embodiments, taxane is taxol.In some embodiments, carrier protein is albumin.In some implementations In mode, the method that the life cycle for extending the individual with melanoma is provided, including give individual effective dose includes containing purple The composition of the nano particle of China fir alcohol and albumin.In some embodiments, method makes the life span extension of individual at least about 1,2,3,4,5,6,7,8,9,10,11,12,18 or any of 24 months.In some embodiments, individual has the IV stages Or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma).In some embodiments, melanoma is metastatic Chromoma.In some embodiments, metastatic melanoma is in M1a stages, M1b stages or M1c stages.In some implementations In mode, metastatic melanoma is in the M1c stages.In some embodiments, melanoma includes the mutation of BRAF.In some implementations In mode, melanoma includes BRAF V600E mutation.In some embodiments, melanoma does not include the mutation of BRAF.One In a little embodiments, melanoma does not include BRAF mutant, and such as activity increases (for example, kinase activity increases and/or and wild type BRAF compared to activity increase) BRAF mutant or the enhanced mutant of BRAF functions.In some embodiments, melanoma is not It is mutated (for example, melanoma includes wild type BRAF) including BRAF V600E.In some embodiments, melanoma includes wild Type BRAF.In some embodiments, melanoma includes BRAF mutant, such as activity increase (for example, kinase activity increase and/ Or compared with wild type BRAF activity increase) BRAF mutant or the enhanced mutant of BRAF functions.In some embodiments In, melanoma includes BRAF V600E mutation.In some embodiments, individual has raised Serum LDH horizontal.At some In embodiment, individual has normal Serum LDH horizontal.In some embodiments, individual has about following any Serum LDH：<0.8×ULN、0.4-0.8×ULN、0.8-1.1×ULN、0.9-1.1×ULN、0.8-1.2×ULN、1.1-1.5 × ULN, 1.2-1.5 × ULN, 1.1-2 × ULN or 1.5-2 × ULN.In some embodiments, individual, which has, is less than about 0.8 The Serum LDH of × ULN.In some embodiments, individual have about 0.8 × to the Serum LDH of about 1.1 × ULN.In some realities It applies in mode, individual has greater than about 1.1 × to the Serum LDH between about 2.0 × ULN.In some embodiments, individual tool Have about 1.1 × to the Serum LDH between about 2.0 × ULN.In some embodiments, individual is people (for example, male or female Property).In some embodiments, taxane is taxol.In some embodiments, carrier protein is albumin.
Monotherapy is can be used as using the method that taxane nano particle treats melanoma to use.In some embodiments In, the method that individual (for example, people) melanoma for the treatment of is provided, including give individual effective dose include containing taxane (for example, Taxol) and carrier protein (for example, albumin) nano particle composition, wherein method uses as monotherapy. In some embodiments, method described herein does not further comprise other therapeutic agents (such as other chemotherapeutics or immunization therapy Agent).In some embodiments, method described herein does not further comprise cytotoxic chemotherapeutic agent.
In some embodiments, the method that individual (for example, people) melanoma for the treatment of is provided, including give (as intravenously Give) individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, About 5mg/ml Nab- taxols), the dosage of taxol is in about 80mg/m wherein in Nanoparticulate compositions2To about 175mg/m2It Between (such as from about 90mg/m2To about 150mg/m2Between).In some embodiments, individual (for example, people) melanoma for the treatment of is provided Method, including give (such as intravenous administration) individual effective dose include the nano particle containing taxol and albumin combination Object (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), wherein the dosage of taxol exists in Nanoparticulate compositions About 90mg/m2To about 150mg/m2Between (for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2), wherein nano particle group Object is closed to be given weekly.In some embodiments, the method that individual (for example, people) melanoma for the treatment of is provided, including give (such as Intravenous administration) individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- taxols, For example, about 5mg/ml Nab- taxols), the dosage of taxol is in about 90mg/m wherein in Nanoparticulate compositions2To about 150mg/m2Between (for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2), wherein Nanoparticulate compositions are given weekly It gives, three in surrounding week.In some embodiments, received the individual human of the treatment for melanoma before treatment is provided The method of melanoma, including it includes the nano particle containing taxol and albumin to give (such as intravenous administration) individual effective dose Composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), taxol wherein in Nanoparticulate compositions Dosage is in about 90mg/m2To about 150mg/m2Between (for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2), wherein nanometer Particulate composition is given weekly, three in surrounding week.In some embodiments, individual human of the treatment without chemotherapy is provided The method of melanoma, including give (such as intravenous administration) individual effective dose includes the nanometer containing taxol and albumin The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of grain, wherein taxol in Nanoparticulate compositions Dosage in about 90mg/m2To about 150mg/m2Between (for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2), wherein receiving Rice grain composition is given weekly, three in surrounding week.In some embodiments, individual is male.In some embodiment party In formula, individual is women.In some embodiments, individual is at least 65 years old people (including for example, at least 70,75 or 80 Year).In some embodiments, individual be less than 65 years old people (including for example, less than 60,50 or 40 years old).
In some embodiments, providing the metastatic melanoma for the treatment of individual (for example, people), (such as IV stage metastatics are black Plain tumor or M1c melanoma) method, including give (such as intravenous administration) individual effective dose include contain taxol and white egg The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of white nano particle, wherein nano particle combine The dosage of taxol is in about 80mg/m in object2To about 175mg/m2Between (such as from about 90mg/m2To about 150mg/m2Between).One In a little embodiments, the metastatic melanoma (such as IV stages melanoma or M1c melanoma) that treatment individual (for example, people) is provided Method, including give (such as intravenous administration) individual effective dose includes containing taxol and albumin (such as Nab- taxols, example Such as, about 5mg/ml Nab- taxols) nano particle composition, wherein the dosage of taxol exists in Nanoparticulate compositions About 90mg/m2To about 150mg/m2Between (for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2), wherein nano particle group Object is closed to be given weekly.In some embodiments, metastatic melanoma (such as IV stages for the treatment of individual (for example, people) are provided Metastatic melanoma or M1c melanoma) method, including give (such as intravenous administration) individual effective dose include contain Japanese yew The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of the nano particle of alcohol and albumin, wherein nanometer The dosage of taxol is in about 90mg/m in particulate composition2To about 150mg/m2Between (for example, about 90mg/m2, about 120mg/m2 Or about 150mg/m2), wherein Nanoparticulate compositions are given weekly, three in surrounding week.In some embodiments, it provides Treatment before received for melanoma treatment individual human metastatic melanoma (such as IV stages metastatic melanoma or M1c melanoma) method, including give (such as intravenous administration) individual effective dose includes receiving containing taxol and albumin The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of rice grain is purple wherein in Nanoparticulate compositions The dosage of China fir alcohol is in about 90mg/m2To about 150mg/m2Between (for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2), Middle Nanoparticulate compositions are given weekly, three in surrounding week.In some embodiments, people of the treatment without chemotherapy is provided Individual metastatic melanoma (such as IV stages metastatic melanoma or M1c melanoma) method, including give (as intravenously to Give) individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), the dosage of taxol is in about 90mg/m wherein in Nanoparticulate compositions2To about 150mg/m2Between (for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2), wherein Nanoparticulate compositions are given weekly, in surrounding Three weeks.In some embodiments, individual is male.In some embodiments, individual is women.In some embodiments In, individual is at least 65 years old people (including for example, at least 70,75 or 80 years old).In some embodiments, individual is less than 65 years old people (including for example, less than 60,50 or 40 years old).
In some embodiments, the method that treatment includes individual (for example, people) melanoma of wild type BRAF, packet are provided Include give (such as intravenous administration) individual effective dose include the composition of the nano particle containing taxol and albumin (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), the dosage of taxol is about wherein in Nanoparticulate compositions 80mg/m2To about 175mg/m2Between (such as from about 90mg/m2To about 150mg/m2Between).In some embodiments, treatment is provided The method of the melanoma of individual (for example, people) including wild type BRAF, including give (such as intravenous administration) individual effective dose Include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ml Nab- are purple China fir alcohol), the dosage of taxol is in about 90mg/m wherein in Nanoparticulate compositions2To about 150mg/m2Between (for example, about 90mg/ m2, about 120mg/m2Or about 150mg/m2), wherein Nanoparticulate compositions are given weekly.In some embodiments, it provides Treatment includes the method for the melanoma of the individual (for example, people) of wild type BRAF, including gives (such as intravenous administration) individual and have Effect amount include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), the dosage of taxol is in about 90mg/m wherein in Nanoparticulate compositions2To about 150mg/m2Between (for example, About 90mg/m2, about 120mg/m2Or about 150mg/m2), wherein Nanoparticulate compositions are given weekly, three in surrounding week. In some embodiments, the individual (example that treatment includes wild type BRAF and received the treatment for melanoma before is provided Such as, people) melanoma method, including give (such as intravenous administration) individual effective dose include contain taxol and albumin Nano particle composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), wherein Nanoparticulate compositions The dosage of middle taxol is in about 90mg/m2To about 150mg/m2Between (for example, about 90mg/m2, about 120mg/m2Or about 150mg/ m2), wherein Nanoparticulate compositions are given weekly, three in surrounding week.In some embodiments, it includes wild to provide treatment The method of raw type BRAF and the melanoma of the individual (for example, people) without chemotherapy, including give (such as intravenous administration) individual A effective amount of includes composition (such as Nab- taxols, for example, about 5mg/ml of the nano particle containing taxol and albumin Nab- taxols), the dosage of taxol is in about 90mg/m wherein in Nanoparticulate compositions2To about 150mg/m2Between (for example, About 90mg/m2, about 120mg/m2Or about 150mg/m2), wherein Nanoparticulate compositions are given weekly, three in surrounding week. In some embodiments, individual is male.In some embodiments, individual is women.In some embodiments, individual is At least 65 years old people (including for example, at least 70,75 or 80 years old).In some embodiments, individual is less than 65 years old people (including for example, less than 60,50 or 40 years old).
In some embodiments, the melanoma that treatment includes the individual (for example, people) of BRAF V600E mutation is provided Method, including give (such as intravenous administration) individual effective dose include the nano particle containing taxol and albumin combination Object (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), wherein the dosage of taxol exists in Nanoparticulate compositions About 80mg/m2To about 175mg/m2Between (such as from about 90mg/m2To about 150mg/m2Between).In some embodiments, it provides and controls The method for treating the melanoma for the individual (for example, people) for including BRAF V600E mutation, including give (such as intravenous administration) individual A effective amount of includes composition (such as Nab- taxols, for example, about 5mg/ml of the nano particle containing taxol and albumin Nab- taxols), the dosage of taxol is in about 90mg/m wherein in Nanoparticulate compositions2To about 150mg/m2Between (for example, About 90mg/m2, about 120mg/m2Or about 150mg/m2), wherein Nanoparticulate compositions are given weekly.In some embodiments In, the method that the melanoma for the individual (for example, people) that treatment includes BRAF V600E mutation is provided, including give (as intravenously Give) individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, About 5mg/ml Nab- taxols), the dosage of taxol is in about 90mg/m wherein in Nanoparticulate compositions2To about 150mg/m it Between2(for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2), wherein Nanoparticulate compositions are given weekly, in surrounding Three weeks.In some embodiments, it includes that BRAF V600E are mutated and received to be directed to melanoma before to provide treatment The method of the melanoma of the individual (for example, people) for the treatment of, including give (such as intravenous administration) individual effective dose includes containing The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of the nano particle of taxol and albumin, wherein The dosage of taxol is in about 90mg/m in Nanoparticulate compositions2To about 150mg/m2Between (for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2), wherein Nanoparticulate compositions are given weekly, three in surrounding week.In some embodiments In, treatment is provided and includes the method for BRAF V600E mutation and the melanoma of the individual (for example, people) without chemotherapy, including is given Give (such as intravenous administration) individual effective dose includes composition (such as Nab- purples of the nano particle containing taxol and albumin China fir alcohol, for example, about 5mg/ml Nab- taxols), the dosage of taxol is in about 90mg/m wherein in Nanoparticulate compositions2Extremely About 150mg/m2Between (for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2), wherein Nanoparticulate compositions are by weekly It gives, three in surrounding week.In some embodiments, individual is male.In some embodiments, individual is women. In some embodiments, individual is at least 65 years old people (including for example, at least 70,75 or 80 years old).In some embodiments In, individual be less than 65 years old people (including for example, less than 60,50 or 40 years old).
In some embodiments, the metastatic melanoma that treatment includes the individual (for example, people) of wild type BRAF is provided The method of (such as IV stages metastatic melanoma or M1c melanoma), including give the packet of (such as intravenous administration) individual effective dose Include composition (such as Nab- taxols, for example, about 5mg/ml Nab- Japanese yews of the nano particle containing taxol and albumin Alcohol), the dosage of taxol is in about 80mg/m wherein in Nanoparticulate compositions2To about 175mg/m2Between (such as from about 90mg/m2Extremely About 150mg/m2Between).In some embodiments, the transfer that treatment includes the individual (for example, people) of wild type BRAF is provided The method of property melanoma (such as IV stages metastatic melanoma or M1c melanoma), including give (such as intravenous administration) individual and have Effect amount include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), the dosage of taxol is in about 90mg/m wherein in Nanoparticulate compositions2To about 150mg/m2Between (for example, About 90mg/m2, about 120mg/m2Or about 150mg/m2), wherein Nanoparticulate compositions are given weekly.In some embodiments In, provide treatment include wild type BRAF individual (for example, people) metastatic melanoma (such as IV stages metastatic melanoma or M1c melanoma) method, including give (such as intravenous administration) individual effective dose includes receiving containing taxol and albumin The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of rice grain is purple wherein in Nanoparticulate compositions The dosage of China fir alcohol is in about 90mg/m2To about 150mg/m2Between (for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2), Middle Nanoparticulate compositions are given weekly, three in surrounding week.In some embodiments, it includes wild type to provide treatment BRAF and (such as the IV stages shift for the metastatic melanoma of individual (for example, people) that received before for the treatment of melanoma Property melanoma or M1c melanoma) method, including give (such as intravenous administration) individual effective dose include containing taxol and The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of the nano particle of albumin, wherein nano particle The dosage of taxol is in about 90mg/m in composition2To about 150mg/m2Between (for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2), wherein Nanoparticulate compositions are given weekly, three in surrounding week.In some embodiments, treatment is provided Metastatic melanoma (such as IV stage metastatic melanomas of individual (for example, people) including wild type BRAF and without chemotherapy Or M1c melanoma) method, including give (such as intravenous administration) individual effective dose includes containing taxol and albumin The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of nano particle, wherein in Nanoparticulate compositions The dosage of taxol is in about 90mg/m2To about 150mg/m2Between (for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2), Wherein Nanoparticulate compositions are given weekly, three in surrounding week.In some embodiments, individual is male.At some In embodiment, individual is women.In some embodiments, individual is at least 65 years old people (including for example, at least 70,75 Or 80 years old).In some embodiments, individual be less than 65 years old people (including for example, less than 60,50 or 40 years old).
In some embodiments, the metastatic for providing the individual (for example, people) that treatment includes BRAF V600E mutation is black The method of plain tumor (such as IV stages metastatic melanoma or M1c melanoma), including give (such as intravenous administration) individual effective dose Include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ml Nab- are purple China fir alcohol), the dosage of taxol is in about 80mg/m wherein in Nanoparticulate compositions2To about 175mg/m2Between (such as from about 90mg/m2 To about 150mg/m2Between).In some embodiments, the individual (for example, people) that treatment includes BRAF V600E mutation is provided Metastatic melanoma (such as IV stages metastatic melanoma or M1c melanoma) method, including give (such as intravenous administration) Individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ Ml Nab- taxols), the dosage of taxol is in about 90mg/m wherein in Nanoparticulate compositions2To about 150mg/m2Between (example Such as, about 90mg/m2, about 120mg/m2Or about 150mg/m2), wherein Nanoparticulate compositions are given weekly.In some embodiment party In formula, it includes that (such as IV stage metastatics are black for the metastatic melanoma of the individual (for example, people) that BRAF V600E are mutated to provide treatment Plain tumor or M1c melanoma) method, including give (such as intravenous administration) individual effective dose include contain taxol and white egg The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of white nano particle, wherein nano particle combine The dosage of taxol is in about 90mg/m in object2To about 150mg/m2Between (for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2), wherein Nanoparticulate compositions are given weekly, three in surrounding week.In some embodiments, treatment is provided Received including BRAF V600E mutation and before the metastatic melanoma for being directed to the individual (for example, people) of the treatment of melanoma The method of (such as IV stages metastatic melanoma or M1c melanoma), including give the packet of (such as intravenous administration) individual effective dose Include composition (such as Nab- taxols, for example, about 5mg/ml Nab- Japanese yews of the nano particle containing taxol and albumin Alcohol), the dosage of taxol is in about 90mg/m wherein in Nanoparticulate compositions2To about 150mg/m2Between (for example, about 90mg/ m2, about 120mg/m2Or about 150mg/m2), wherein Nanoparticulate compositions are given weekly, three in surrounding week.In some realities It applies in mode, the metastatic melanoma that treatment includes BRAF V600E mutation and the individual (for example, people) without chemotherapy is provided The method of (such as IV stages metastatic melanoma or M1c melanoma), including give the packet of (such as intravenous administration) individual effective dose Include composition (such as Nab- taxols, for example, about 5mg/ml Nab- Japanese yews of the nano particle containing taxol and albumin Alcohol), the dosage of taxol is in about 90mg/m wherein in Nanoparticulate compositions2To about 150mg/m2Between (for example, about 90mg/ m2, about 120mg/m2Or about 150mg/m2), wherein Nanoparticulate compositions are given weekly, three in surrounding week.In some realities It applies in mode, individual is male.In some embodiments, individual is women.In some embodiments, individual is at least 65 The people (including for example, at least 70,75 or 80 years old) in year.In some embodiments, individual is less than 65 years old people's (including example Such as, be less than 60,50 or 40 years old).
In some embodiments, metastatic melanoma (such as IV stages turn in the liver for the treatment of individual (for example, people) are provided Shifting property melanoma or M1c melanoma) method, including give and (such as given by hepatic arterial infusion) individual effective dose including containing There is the composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of the nano particle of taxol and albumin, The dosage of taxol is in about 80mg/m in middle Nanoparticulate compositions2To about 175mg/m2Between (such as from about 90mg/m2To about 150mg/m2Between).In some embodiments, it provides in the liver of individual (for example, people) that treatment includes wild type BRAF The method of metastatic melanoma (such as IV stages metastatic melanoma or M1c melanoma), including give and (such as pass through hepatic arterial infusion Give) individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, About 5mg/ml Nab- taxols), the dosage of taxol is in about 80mg/m wherein in Nanoparticulate compositions2To about 175mg/m2It Between (such as from about 90mg/m2To about 150mg/m2Between).In some embodiments, Nanoparticulate compositions are given weekly.One In a little embodiments, Nanoparticulate compositions are given weekly, three in surrounding week.In some embodiments, individual is man Property.In some embodiments, individual is women.In some embodiments, individual be at least 65 years old people (including for example, At least 70,75 or 80 years old).In some embodiments, individual be less than 65 years old people (including for example, be less than 60,50 or 40 Year).
In some embodiments, the metastatic in the liver for the individual (for example, people) that treatment includes wild type BRAF is provided The method of melanoma (such as IV stages metastatic melanoma or M1c melanoma), including give and (such as given by hepatic arterial infusion) Individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ Ml Nab- taxols), wherein Nab- dose of paclitaxel is in about 130mg/m2To about 285mg/m2Between (e.g., for example, about 130mg/ m2, about 170mg/m2, about 220mg/m2Or about 285mg/m2).In some embodiments, it includes BRAF V600E to provide treatment The side of metastatic melanoma (such as IV stages metastatic melanoma or M1c melanoma) in the liver of the individual (for example, people) of mutation Method, including give and (such as given by hepatic arterial infusion) individual effective dose includes the nano particle containing taxol and albumin Composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), wherein Nab- dose of paclitaxel is in about 130mg/ m2To about 285mg/m2Between (e.g., for example, about 130mg/m2, about 170mg/m2, about 220mg/m2Or about 285mg/m2).At some In embodiment, Nanoparticulate compositions every three Monday day is given by arteria hepatica.In some embodiments, nano particle group Object is closed to give by hepatic arterial infusion through 30 minutes within every three weeks.In some embodiments, individual is at least 65 years old people (packet It includes, for example, at least 70,75 or 80 years old).In some embodiments, individual is less than 65 years old people and (including for example, is less than 60,50 or 40 years old).
In some embodiments, metastatic melanoma (such as IV stages turn in the liver for the treatment of individual (for example, people) are provided Shifting property melanoma or M1c melanoma) method, including give and (such as given by hepatic arterial infusion) individual effective dose including containing There is the composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of the nano particle of taxol and albumin, The dosage of taxol is in about 80mg/m in middle Nanoparticulate compositions2To about 175mg/m2Between (such as from about 100mg/m2To about 150mg/m2Between).In some embodiments, the liver that treatment includes the individual (for example, people) of BRAF V600E mutation is provided In metastatic melanoma (such as IV stages metastatic melanoma or M1c melanoma) method, including give and (such as pass through arteria hepatica Perfusion give) individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- taxols, example Such as, about 5mg/ml Nab- taxols), the dosage of taxol is in about 80mg/m wherein in Nanoparticulate compositions2To about 175mg/ m2Between (such as from about 100mg/m2To about 150mg/m2Between).In some embodiments, Nanoparticulate compositions are given weekly It gives.In some embodiments, Nanoparticulate compositions are given weekly, three in surrounding week.In some embodiments, a Body is male.In some embodiments, individual is women.In some embodiments, individual is at least 65 years old people (packet It includes, for example, at least 70,75 or 80 years old).In some embodiments, individual is less than 65 years old people and (including for example, is less than 60,50 or 40 years old).
In some embodiments, uveal melanoma (such as unresectable grape for the treatment of individual (for example, people) is provided Film melanoma or metastatic uveal melanoma) method, including give (such as intravenous administration) individual effective dose include contain There is the composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of the nano particle of taxol and albumin. In some embodiments, uveal melanoma is any one of choroidal melanoma, ciliary autologous melanoma or iris melanoma. In some embodiments, uveal melanoma is rear uveal melanoma.
In some embodiments, the method that the uveal melanoma for the treatment of individual (for example, people) is provided, including give (such as intravenous administration) individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- Japanese yews Alcohol, for example, about 5mg/ml Nab- taxols), the dosage of taxol is in about 80mg/m wherein in Nanoparticulate compositions2To about 175mg/m2Between (such as from about 100mg/m2To about 150mg/m2Between).In some embodiments, provide treatment individual (for example, People) metastatic uveal melanoma method, including give (such as intravenous administration) individual effective dose include contain Japanese yew The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of the nano particle of alcohol and albumin, wherein nanometer The dosage of taxol is in about 80mg/m in particulate composition2To about 175mg/m2Between (such as from about 100mg/m2To about 150mg/m2It Between).In some embodiments, the method that individual (for example, people) the unresectable uveal melanoma for the treatment of is provided, including give Give (such as intravenous administration) individual effective dose includes composition (such as Nab- purples of the nano particle containing taxol and albumin China fir alcohol, for example, about 5mg/ml Nab- taxols), the dosage of taxol is in about 80mg/m wherein in Nanoparticulate compositions2Extremely About 175mg/m2Between (such as from about 100mg/m2To about 150mg/m2Between).In some embodiments, Nanoparticulate compositions quilt It gives weekly.In some embodiments, Nanoparticulate compositions are given weekly, three in surrounding week.In some embodiment party In formula, Nanoparticulate compositions are by intravenous administration.In some embodiments, Nanoparticulate compositions are weekly in 150mg/m2 Dosage under through 30 minutes by intravenous administration.In some embodiments, Nanoparticulate compositions three weeks in surrounding are every Week is in 150mg/m2Dosage under through 30 minutes by intravenous administration.In some embodiments, individual includes wild type BRAF. In some embodiments, individual includes that BRAF is mutated.In some embodiments, individual includes BRAF V600E mutation. In some embodiments, individual is male.In some embodiments, individual is women.In some embodiments, individual is At least 65 years old people (including for example, at least 70,75 or 80 years old).In some embodiments, individual is less than 65 years old people (including for example, less than 60,50 or 40 years old).
In some embodiments, the method that the uveal melanoma for the treatment of individual (for example, people) is provided, including give (such as intravenous administration) individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- Japanese yews Alcohol, for example, about 5mg/ml Nab- taxols), the dosage of taxol is in about 80mg/m wherein in Nanoparticulate compositions2To about 175mg/m2Between (such as from about 100mg/m2To about 150mg/m2Between).In some embodiments, provide treatment individual (for example, People) metastatic uveal melanoma method, including give (such as intravenous administration) individual effective dose include contain Japanese yew The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of the nano particle of alcohol and albumin, wherein nanometer The dosage of taxol is in about 80mg/m in particulate composition2To about 175mg/m2Between (such as from about 100mg/m2To about 150mg/m2It Between).In some embodiments, the method that individual (for example, people) the unresectable uveal melanoma for the treatment of is provided, including give Give (such as intravenous administration) individual effective dose includes composition (such as Nab- purples of the nano particle containing taxol and albumin China fir alcohol, for example, about 5mg/ml Nab- taxols), the dosage of taxol is in about 80mg/m wherein in Nanoparticulate compositions2Extremely About 175mg/m2Between (such as from about 100mg/m2To about 150mg/m2Between).In some embodiments, Nanoparticulate compositions quilt It gives weekly.In some embodiments, Nanoparticulate compositions are given weekly, three in surrounding week.In some embodiment party In formula, individual includes BRAF V600E mutation.In some embodiments, individual is male.In some embodiments, individual It is women.In some embodiments, individual is at least 65 years old people (including for example, at least 70,75 or 80 years old).At some In embodiment, individual be less than 65 years old people (including for example, less than 60,50 or 40 years old).
In some embodiments, the method that treatment individual human melanoma is provided, including to give (such as intravenous administration) a Body is a effective amount of include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), the dosage of taxol is in about 80mg/m wherein in Nanoparticulate compositions2To about 175mg/m2Between (such as from about 100mg/m2To about 150mg/m2Between, for example, 150mg/m2), wherein Nanoparticulate compositions are given weekly, in surrounding Three weeks.In some embodiments, the method that the IV stage cutaneous melanomas for the treatment of individual human are provided, including give (such as vein Inside give) individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- taxols, example Such as, about 5mg/ml Nab- taxols), the dosage of taxol is in about 100mg/m wherein in Nanoparticulate compositions2To about 150mg/m2Between (for example, 150mg/m2), wherein Nanoparticulate compositions are given weekly, three in surrounding week.In some realities Apply in mode, provide treatment the individual human without chemotherapy IV stage cutaneous melanomas method, including give (as intravenously to Give) individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), the dosage of taxol is in about 100mg/m wherein in Nanoparticulate compositions2To about 150mg/m2It Between (for example, 150mg/m2), wherein Nanoparticulate compositions are given weekly, three in surrounding week.In some embodiments, There is provided treatment the individual human without chemotherapy IV stage cutaneous melanomas method, wherein individual have recorded radiation image can The property surveyed disease (for example, by least one recorded radiation image survey lesion there are by determine), including give (such as vein Inside give) individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- taxols, example Such as, about 5mg/ml Nab- taxols), the dosage of taxol is in about 100mg/m wherein in Nanoparticulate compositions2To about 150mg/m2Between (for example, 150mg/m2), wherein Nanoparticulate compositions are given weekly, three in surrounding week.In some realities It applies in mode, individual has the metastatic melanoma in M1c stages.In some embodiments, individual has M1c the or M1b stages Metastatic melanoma.In some embodiments, individual has the metastatic melanoma in M1a, M1b or M1c stage.At some In embodiment, individual has LDH levels (such as LDH no more than about 2.0 × ULN<About 0.8 × ULN, about 0.8 to about 1.1 × ULN or>About 1.1-2 × ULN).In some embodiments, individual includes wild type BRAF.In some embodiments, individual It is mutated with BRAF.In some embodiments, individual has BRAF V600E mutation.In some embodiments, individual is Male.In some embodiments, individual is women.In some embodiments, individual is at least 65 years old people (including example Such as, at least 70,75 or 80 years old).In some embodiments, individual be less than 65 years old people (including for example, less than 60,50 or 40 years old).
In some embodiments, the method that treatment individual human melanoma is provided, including to give (such as intravenous administration) a Body is a effective amount of include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), the dosage of taxol is in about 80mg/m wherein in Nanoparticulate compositions2To about 175mg/m2Between (such as from about 100mg/m2To about 150mg/m2Between, for example, 150mg/m2), wherein Nanoparticulate compositions are given weekly, in surrounding Three weeks, and wherein individual is substantially refractory in preceding BRAF inhibitor for treating.In some embodiments, treatment people is provided The method of the IV stage cutaneous melanomas of individual, including give (such as intravenous administration) individual effective dose includes containing taxol With the composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of the nano particle of albumin, wherein nanometer The dosage of taxol is in about 100mg/m in grain composition2To about 150mg/m2Between (for example, 150mg/m2), wherein nano particle Composition is given weekly, three in surrounding week, and wherein individual is substantially refractory in preceding BRAF inhibitor for treating.
In some embodiments, the method that the metastatic melanoma for the individual human that treatment includes wild type BRAF is provided, Including give (such as intravenous administration) individual effective dose include the composition of the nano particle containing taxol and albumin (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), the dosage of taxol is about wherein in Nanoparticulate compositions 80mg/m2To about 175mg/m2Between (such as from about 100mg/m2To about 150mg/m2Between, for example, 150mg/m2), wherein nanometer Grain composition is given weekly, three in surrounding week.In some embodiments, the treatment people with wild type BRAF is provided The unresectable IIIc stages of body or the method for IV stage metastatic melanomas, including give (such as intravenous administration) individual and have Effect amount include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), the dosage of taxol is in about 100mg/m wherein in Nanoparticulate compositions2To about 150mg/m2Between (for example, 150mg/m2), wherein Nanoparticulate compositions are given weekly, three in surrounding week.In some embodiments, treatment is provided The unresectable IIIc stages of individual human with wild type BRAF or the method for IV stage metastatic melanomas --- wherein Her wooden monoclonal antibody failure in treatment of individual, including give (such as intravenous administration) individual effective dose includes containing taxol and white The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of the nano particle of albumen, wherein nano particle group The dosage of taxol in object is closed in about 100mg/m2To about 150mg/m2Between (for example, 150mg/m2), wherein nano particle combines Object is given weekly, three in surrounding week.In some embodiments, individual has the metastatic melanoma in M1c stages.One In a little embodiments, individual has the metastatic melanoma in M1c or M1b stages.In some embodiments, individual have M1a, The metastatic melanoma in M1b or M1c stages.In some embodiments, individual has the LDH no more than about 2.0 × ULN horizontal (such as LDH<About 0.8 × ULN, about 0.8 to about 1.1 × ULN or>About 1.1-2 × ULN).In some embodiments, individual is man Property.In some embodiments, individual is women.In some embodiments, individual be at least 65 years old people (including for example, At least 70,75 or 80 years old).In some embodiments, individual be less than 65 years old people (including for example, be less than 60,50 or 40 Year).
In some embodiments, the method for treating melanoma by following any therapeutic regimen that table 3 provides is provided.
The clinical research of 3. Nab- taxol monotherapies of table
Method described herein can further comprise that the patient that selection is treated (is suitable for melanoma therapy for example, identifying Individual).Thus, for example, in some embodiments, method described herein further comprises that identification has spy described herein The sign individual of one of them, melanoma hypotype as described herein or by stages feature, LDH levels or BRAF states.In some realities It applies in mode, the method that individual (for example, people) melanoma for the treatment of is provided, including step：(a) determine whether individual has melanocyte Tumor, melanoma as described herein, and (b) give individual effective dose include contain taxane (for example, taxol) and carrier egg The composition of the nano particle of (for example, albumin) in vain.In some embodiments, provide treatment individual (for example, people) melanocyte The method of tumor, including step：(a) it determines whether individual has BRAF states as described herein, and (b) gives individual effective dose Composition including the nano particle for containing taxane (for example, taxol) and carrier protein (for example, albumin).In some realities It applies in mode, the method that individual (for example, people) melanoma for the treatment of is provided, including step：(a) determine whether individual has this paper institutes The LDH that states is horizontal, and (b) give individual effective dose include containing taxane (for example, taxol) and carrier protein (for example, Albumin) nano particle composition.
In some embodiments, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, including give Individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ Ml Nab- taxols), wherein based on melanoma hypotype or by stages feature (such as M1a, M1b, M1c stage) selection individual controlled It treats.In some embodiments, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, including：A) it determines a The melanoma hypotype of body or by stages feature (such as M1a, M1b, M1c stage)；And b) give individual effective dose includes containing Japanese yew The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of the nano particle of alcohol and albumin.In some realities It applies in mode, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, including：A) melanoma based on individual Hypotype or by stages feature (such as M1a, M1b, M1c stage) selection individual are treated；And b) give individual effective dose includes containing There is the composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of the nano particle of taxol and albumin. In some embodiments, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, including：A) individual is determined Melanoma hypotype or by stages feature (such as M1a, M1b, M1c stage)；B) melanoma hypotype based on individual or feature is (such as by stages M1a, M1b, M1c stage)) select individual to be treated；And c) give individual effective dose includes containing taxol and albumin Nano particle composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols).In some embodiments, it controls Treat the individual with M1a stage melanoma.In some embodiments, individual of the treatment with M1b stage melanoma.At some In embodiment, the individual with M1c stage melanoma is treated.In some embodiments, treatment has cutaneous metastatic black The individual of plain tumor.Treatment determines can also be based on the hypotype of melanoma, any melanoma hypotype as described herein.In some implementations In mode, method is included in the 1st, 8, the 15 day intravenous administration (for example, through about 30 to about 40 minutes) in every 28 day period The Nab- taxols (such as from about 5mg/ml Nab- taxols) of individual effective dose, the agent of taxol wherein in Nanoparticulate compositions Amount is about 80 to about 200mg/m2(including for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2).In some embodiment party In formula, treatment individual at least about 2 months, including, for example, any of at least about 3,4,5,6,7,8,9,10,11 or 12 months.
In some embodiments, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, including give Individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ Ml Nab- taxols), wherein based on melanoma hypotype or by stages characterized by the M1c stages, individual is selected to be treated.At some In embodiment, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, including：A) melanocyte of individual is determined Tumor hypotype or by stages feature (such as M1a, M1b, M1c stage)；And b) give individual effective dose includes containing taxol and white egg The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of white nano particle, wherein if individual has The melanoma in M1c stages then selects the individual to be treated.In some embodiments, treatment autologous melanoma (example is provided Such as, metastatic melanoma) method, including：A) the M1c stages are in based on melanoma hypotype, individual is selected to be treated；And b) Give individual effective dose includes composition (such as Nab- taxols, for example, about of the nano particle containing taxol and albumin 5mg/ml Nab- taxols).In some embodiments, the side for the treatment of autologous melanoma (for example, metastatic melanoma) is provided Method, including：A) individual melanoma hypotype or by stages feature (such as M1a, M1b, M1c stage) are determined；B) it is based on melanoma hypotype In the M1c stages, individual is selected to be treated；And c) give individual effective dose includes the nanometer containing taxol and albumin The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of particle.In some embodiments, treatment has The individual of cutaneous metastatic melanoma.In some embodiments, method is included in the 1st, 8, the 15 day vein in every 28 day period Inside give Nab- taxols (the such as from about 5mg/ml Nab- Japanese yews of (for example, through about 30 to about 40 minutes) individual effective dose Alcohol), the dosage of taxol is about 80 to about 200mg/m wherein in Nanoparticulate compositions2(including for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2).In some embodiments, treatment individual at least about 2 months, including, for example, at least about 3, 4,5,6,7,8,9,10,11 or any of 12 months.
In some embodiments, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, including give Individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ Ml Nab- taxols), wherein the BRAF states based on individual, select individual to be treated.In some embodiments, it provides The method for the treatment of autologous melanoma (for example, metastatic melanoma), including：A) the BRAF states of individual are determined；And it b) gives a Body is a effective amount of include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols).In some embodiments, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, packet It includes：A) the BRAF states of individual are determined；B) the BRAF states based on individual, select individual to be treated；And it c) gives individual and has Effect amount include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols).In some embodiments, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, packet It includes：A) the BRAF states based on individual, select individual to be treated；And b) give individual effective dose include containing taxol and The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of the nano particle of albumin.In some embodiment party In formula, treatment includes the individual of wild type BRAF.In some embodiments, treatment includes BRAF mutation (such as BRAF V600E Mutation) individual.It is also contemplated for the treatment based on any other BRAF state described herein.In some embodiments, method packet Include the 1st, 8,15 day intravenous administration (for example, through about 30 to about 40 minutes) individual effective dose in every 28 day period Nab- taxols (such as from about 5mg/ml Nab- taxols), the dosage of taxol is about 80 to about wherein in Nanoparticulate compositions 200mg/m2(including for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2).In some embodiments, treatment individual At least about 2 months, including, for example, any of at least about 3,4,5,6,7,8,9,10,11 or 12 months.
In some embodiments, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, including give Individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ Ml Nab- taxols), wherein if individual includes wild type BRAF, the individual is selected to be treated.In some embodiments In, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, including：A) the BRAF states of individual are determined；And b) Give individual effective dose includes composition (such as Nab- taxols, for example, about of the nano particle containing taxol and albumin 5mg/ml Nab- taxols), wherein if individual includes wild type BRAF, the individual is selected to be treated.In some implementations In mode, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, including：A) it includes wild type to be based on individual BRAF selects individual to be treated；And b) give individual effective dose includes the nano particle containing taxol and albumin Composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols).In some embodiments, it is black to provide treatment individual The method of plain tumor (for example, metastatic melanoma), including：A) the BRAF states of individual are determined；B) it includes wild type to be based on individual BRAF selects individual to be treated；And c) give individual effective dose includes the nano particle containing taxol and albumin Composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols).In some embodiments, method is included in every 28 The Nab- taxols of 1st, 8,15 day intravenous administration (for example, through about 30 to the about 40 minutes) individual effective dose in its period (such as from about 5mg/ml Nab- taxols), the dosage of taxol is about 80 to about 200mg/m wherein in Nanoparticulate compositions2(packet It includes, for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2).In some embodiments, treatment individual at least about 2 Month, including, for example, any of at least about 3,4,5,6,7,8,9,10,11 or 12 months.
In some embodiments, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, including give Individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ Ml Nab- taxols), wherein if individual, which includes BRAF, is mutated (such as BRAF V600E mutation), the individual is selected to be controlled It treats.In some embodiments, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, including：A) it determines a The BRAF states of body；And b) give individual effective dose include the composition of the nano particle containing taxol and albumin (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), wherein if individual includes that (such as BRAF V600E are prominent for BRAF mutation Become), then select the individual to be treated.In some embodiments, treatment autologous melanoma is provided (for example, metastatic melanocyte Tumor) method, including：A) it includes that BRAF is mutated (such as BRAF V600E mutation) to be based on individual, and individual is selected to be treated；And b) Give individual effective dose includes composition (such as Nab- taxols, for example, about of the nano particle containing taxol and albumin 5mg/ml Nab- taxols).In some embodiments, the side for the treatment of autologous melanoma (for example, metastatic melanoma) is provided Method, including：A) the BRAF states of individual are determined；B) it includes that BRAF is mutated (such as BRAF V600E mutation) to be based on individual, selection Body is treated；And c) give individual effective dose include the composition of the nano particle containing taxol and albumin (such as Nab- taxols, for example, about 5mg/ml Nab- taxols).In some embodiments, method is included in every 28 day period The Nab- taxols of the 1st, 8,15 day intravenous administration (for example, through about 30 to about 40 minutes) individual effective dose are (such as from about 5mg/ml Nab- taxols), the dosage of taxol is about 80 to about 200mg/m wherein in Nanoparticulate compositions2(including example Such as, about 90mg/m2, about 120mg/m2Or about 150mg/m2).In some embodiments, treatment individual at least about 2 months, packet It includes, for example, any of at least about 3,4,5,6,7,8,9,10,11 or 12 months.
In some embodiments, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, including give Individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ Ml Nab- taxols), wherein the horizontally selected individuals of LDH based on individual are treated.In some embodiments, it provides and controls The method for treating an autologous melanoma (for example, metastatic melanoma), including：A) determine that the LDH of individual is horizontal；And it b) gives individual and has Effect amount include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols).In some embodiments, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, packet It includes：A) the horizontally selected individuals of LDH based on individual are treated；And b) give individual effective dose includes containing taxol and white The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of the nano particle of albumen.In some embodiments In, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, including：A) determine that the LDH of individual is horizontal；B) base It is treated in the horizontally selected individuals of LDH of individual；And c) give individual effective dose includes containing taxol and albumin The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of nano particle.In some embodiments, it treats LDH levels are greater than about 1.1 to about 2.0x ULN individual.In some embodiments, LDH levels are treated in about 0.8x to about Individual between 1.1x ULN.In some embodiments, treatment LDH levels are less than about the individual of 0.8x ULN.Consider treatment Individual with any other LDH levels described herein.In some embodiments, method be included in every 28 day period the 1st, 8, Nab- taxols (the such as from about 5mg/ml of 15 days intravenous administration (for example, through about 30 to about 40 minutes) individual effective doses Nab- taxols), the dosage of taxol is about 80 to about 200mg/m wherein in Nanoparticulate compositions2(including for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2).In some embodiments, treatment individual at least about 2 months, including, example Such as, at least about 3,4,5,6,7,8,9,10,11 or any of 12 months.
In some embodiments, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, including give Individual effective dose include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ Ml Nab- taxols), wherein having raised LDH horizontal based on individual, individual is selected to be treated.In some embodiments In, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, including：A) determine that the LDH of individual is horizontal；And b) Give individual effective dose includes composition (such as Nab- taxols, for example, about of the nano particle containing taxol and albumin 5mg/ml Nab- taxols), wherein based on having raised LDH horizontal, individual is selected to be treated.In some embodiments In, the method that treatment autologous melanoma (for example, metastatic melanoma) is provided, including：A) being based on individual has raised LDH water It is flat, select individual to be treated；And b) give individual effective dose include the nano particle containing taxol and albumin group Close object (such as Nab- taxols, for example, about 5mg/ml Nab- taxols).In some embodiments, provide treatment individual melanocyte The method of tumor (for example, metastatic melanoma), including：A) determine that the LDH of individual is horizontal；B) being based on individual has raised LDH Level selects individual to be treated；And c) give individual effective dose includes the nano particle containing taxol and albumin Composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols).In some embodiments, treatment LDH is horizontal big In about 1.1 to about 2.0x ULN individual.In some embodiments, method be included in the 1st, 8,15 day of every 28 day period it is quiet Nab- taxols (the such as from about 5mg/ml Nab- Japanese yews of (for example, through about 30 to about 40 minutes) individual effective dose are given in arteries and veins Alcohol), the dosage of taxol is about 80 to about 200mg/m wherein in Nanoparticulate compositions2(including for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2).In some embodiments, treatment individual at least about 2 months, including, for example, at least about 3, 4,5,6,7,8,9,10,11 or any of 12 months.
In some embodiments, it is treated based on two or more determination individuals in following features：Melanoma Hypotype or by stages feature, BRAF states and LDH are horizontal.For example, in some embodiments, providing treatment autologous melanoma (example Such as, metastatic melanoma) method, including give individual effective dose includes the nano particle containing taxol and albumin Composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), wherein feature is (such as based on melanoma hypotype or by stages M1a, M1b, M1c stage) and BRAF states, select individual to be treated.In some embodiments, provide treatment individual melanocyte The method of tumor (for example, metastatic melanoma), including：A) determine individual melanoma hypotype or by stages feature (such as M1a, M1b, The M1c stages) and BRAF states；And b) give individual effective dose include the nano particle containing taxol and albumin combination Object (such as Nab- taxols, for example, about 5mg/ml Nab- taxols).In some embodiments, the melanocyte for the treatment of individual is provided The method of tumor (for example, metastatic melanoma) and BRAF states includes：A) melanoma hypotype based on individual or feature is (such as by stages M1a, M1b, M1c stage), select individual to be treated；And b) give individual effective dose includes containing taxol and albumin Nano particle composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols).In some embodiments, it carries Include for the method for treating individual melanoma (for example, metastatic melanoma) and BRAF states：A) melanoma of individual is determined Hypotype or by stages feature (such as M1a, M1b, M1c stage) and BRAF states；B) feature based on individual melanoma hypotype or by stages (such as M1a, M1b, M1c stage) selects individual to be treated；And c) give individual effective dose includes containing taxol and white egg The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of white nano particle.In some embodiments, Treat the individual that there is M1a stages melanoma and include wild type BRAF.In some embodiments, treatment has M1b ranks Section melanoma and include wild type BRAF individual.In some embodiments, treatment with M1c stages melanoma and is wrapped Include the individual of wild type BRAF.In some embodiments, of the treatment with cutaneous metastatic melanoma and wild type BRAF Body.Treatment determines can also be based on melanoma hypotype, any melanoma hypotype as described herein, and also considers other BRAF shapes State, any BRAF states as described herein.In some embodiments, method is included in the 1st, 8,15 day of every 28 day period (such as from about 5mg/ml Nab- are purple for the Nab- taxols of intravenous administration (for example, through about 30 to about 40 minutes) individual effective dose China fir alcohol), the dosage of taxol is about 80 to about 200mg/m wherein in Nanoparticulate compositions2(including for example, about 90mg/m2、 About 120mg/m2Or about 150mg/m2).In some embodiments, treatment individual at least about 2 months, including, for example, at least about 3,4,5,6,7,8,9,10,11 or any of 12 months.
In some embodiments, as described herein to treat the method for melanoma as single using taxane nano particle Therapy uses.In some embodiments, do not further comprise other using the method that taxane nano particle treats melanoma Therapeutic agent (such as other chemotherapeutics or immunotherapeutic agent).In some embodiments, method does not further comprise cytotoxicity Treat agent.
It is appreciated that the reference and description of the method for the treatment of melanoma as described herein are exemplary, and the description is same Deng the method for being applicable in and treating melanoma including the use of combined therapy.
Combination therapy
The present invention further provides the combined therapies for the treatment of melanoma.Provided herein is the methods for the treatment of melanoma, including give Give individual effective dose includes the nano particle containing taxane (for example, taxol) and carrier protein (for example, albumin) Composition and the second therapy.Second therapy can be operation, radiation, gene therapy, immunotherapy, bone-marrow transplantation, stem cell shifting Plant, hormonotherapy, targeted therapies, cold therapy, ultrasonic therapy, photodynamic therapy and/or chemotherapy are (for example, can be used for controlling Treat the one or more compounds or its pharmaceutically acceptable salt of melanoma).Nanoparticulate compositions are giving the second therapy Before or after give.
In some embodiments, the method that individual (for example, people) melanoma for the treatment of is provided, including give individual a) effective What is measured includes the composition and b of the nano particle containing taxane (for example, taxol) and carrier protein (for example, albumin)) A effective amount of other agent (such as chemotherapeutics or immunotherapeutic agent) of at least one.In some embodiments, individual has the IV stages Or metastatic melanoma (for example, IV stages or metastatic cutaneous melanoma).In some embodiments, melanoma is metastatic Chromoma.In some embodiments, metastatic melanoma is in M1a stages, M1b stages or M1c stages.In some implementations In mode, metastatic melanoma is in the M1c stages.In some embodiments, melanoma includes the mutation of BRAF.In some implementations In mode, melanoma does not include the mutation of BRAF.In some embodiments, melanoma does not include BRAF mutant, such as activity The BRAF mutant or BRAF functions for increasing (for example, kinase activity increases and/or activity increases compared with wild type BRAF) increase Strong type mutant.In some embodiments, melanoma does not include BRAF V600E mutation (for example, melanoma includes wild type BRAF).In some embodiments, melanoma includes wild type BRAF.In some embodiments, melanoma includes BRAF prominent Variant, such as activity increase (for example, kinase activity increase and/or with wild type BRAF compared with activity increase) BRAF mutant or The enhanced mutant of BRAF functions.In some embodiments, melanoma includes BRAF V600E mutation.In some embodiments In, individual has raised Serum LDH horizontal.In some embodiments, individual has about following any Serum LDH：< 0.8×ULN、0.4-0.8×ULN、0.8-1.1×ULN、0.9-1.1×ULN、0.8-1.2×ULN、1.1-1.5×ULN、 1.2-1.5 × ULN, 1.1-2 × ULN or 1.5-2 × ULN.In some embodiments, individual has less than about 0.8 × ULN's Serum LDH.In some embodiments, individual have about 0.8 × to the Serum LDH of about 1.1 × ULN.In some embodiments In, individual has greater than about 1.1 × to the Serum LDH between about 2.0 × ULN.In some embodiments, individual has about 1.1 × to the Serum LDH between about 2.0 × ULN.In some embodiments, individual is people's (for example, sex). In some embodiments, taxane is taxol.In some embodiments, carrier protein is albumin.In some embodiment party In formula, other agent are chemotherapeutics or immunotherapeutic agent.In some embodiments, other agent are platinum base agent, such as carboplatin.
Provided herein is considered exemplary and non-limiting chemotherapeutics lists.Chemotherapeutics appropriate includes, for example, platinum base Agent (such as carboplatin), vinca alkaloids, the medicament for interrupting micro-pipe formation, anti-angiogenic agent, therapeutic antibodies, EGFR targetings Agent, tyrosine kinase targeting agent (such as tyrosine kinase inhibitor), transition metal complex, proteasome inhibitor, antimetabolic Object (such as nucleoside analog), alkylating agent, anthracycline antibiotic, topoisomerase enzyme inhibitor, macrolides, therapeutic antibodies, Retinoid；Geldanamycin or derivatives thereof and other standards chemotherapeutics well known in the art.
In some embodiments, other agent are one of the following：Platinum base agent (for example, carboplatin or cis-platinum), anti-vegf Antibody (for example, bevacizumab (bevacizumab)), Dacarbazine or DTIC (also referred to as DIC, DTIC-Dome or imidazoles carboxylic Amide), oblimersen (or Genasense), proleulzin (IL-2), interferon (IFN), Interferon Alpha-2b, BRAF inhibitor (the non-Buddhist nun of such as Wella (or Zelboraf), GDC-0879 (being purchased from Tocris Bioscience), PLX-4720 (are purchased from Symansis) or Sorafenib (or Sorafenib Tosylate or Lei Shawa (Nexavar) (are purchased from Bayer Pharmaceuticals Corp.)), darafinib (GSK2118436), LGX-818, CEP-32496, UI-152, RAF 265, Rui Gefeini (BAY 73-4506) or CCT239065), antibody (such as BMS- of anti-programmed death 1 (PD-1) receptor 936558, be purchased from Bristol Myers Squibb), the antibody (anti-PD-L1 antibody) of anti-PD-1 ligands or anti-CTLA-4 it is anti- Body such as her the wooden monoclonal antibody (or MDX-010, MDX-101 or Yervoy) or DNA alkylating agents, such as Temozolomide (Temozolomide)。
Programmed death receptor 1 (PD-I) be the CD28/CTLA4 families expressed in the non-sleep T cell of activation at Member (Nishimura et al. (1996) Int.Immunol.8:773).The cooperation of PD-I and its ligand have mediated inhibition signal, Cause cytokine production to reduce reduces (Nishimura et al. (1999) Immunity 11 with T cell survival rate:141； Nishimura et al.(2001)Science 291:319；Chemnitz et al.(2004)J.Immunol.173: 945)。
Programmed death receptors ligand 1 (PD-Ll) is in various kinds of cell type (T cell for including APC and activation) upper table B7 family members (Yamazaki et al. (2002) J.Immunol.169 reached:5538).PD-Ll combinations PD-I and B7-1.T The combination of the PD-Ll and B7-1 of combination and the T cell expression of the B7-1 and PD-Ll of cell expression cause T cell to inhibit (Butte et al.(2007)Immunity 27:111).It also proves on evidence, such as other B7 family members, PD-Ll also can be to T cell Costimulatory signal (Subudhi et al. (2004) J.Clin.Invest.113 is provided:694；Tamura et al.(2001) Blood 97:1809)。
Trimetinib (Trametinib) (GSK1120212) is protein kinase kinase (the MEK MAPK/ of mitogen activation ERK kinases) orally available ground biological utilisation inhibitor.National Cancer Institute, drug dictionary (WWW cancer.gov/ drugdictionaryCdrid=599034 is accessed in 02/11/2013).Trimetinib specifically combines and inhibits MEK 1 and 2, cause the cellular signal transduction and cell Proliferation of growth factor mediation in various cancers to be suppressed.Ibid.MEK 1 It is bispecific threonine/tyrosine kinase with 2, is usually raised in various cancer cell types, and is adjusted in activation It controls and plays an important roll in the RAS/RAF/MEK/ERK signal transduction paths of cell growth.Ibid.
TH-302 is the pro-drug of anoxic activation, by the 2- nitroimidazole phosphate conjugates with potential anti-tumor activity Composition.National Cancer Institute, drug dictionary (WWW cancer.gov/drugdictionaryCdrID=560194 is visited It asks in 02/11/2013).The 2- nitroimidazole moieties of the pro-drug TH-302 of anoxic activation serve as anoxic trigger, in tumour Released dna alkylation dibromo isophosphoramide mustard part in anoxic zones.Ibid.The anoxic activity specific of this agent is reduced General toxicity.Ibid.
Therefore the method that the application provides combined therapy in some embodiments.In some embodiments, it provides and controls The method for treating the melanoma (such as metastatic melanoma, III stages melanoma or IV stages melanoma) of individual (such as individual human), packet Include that give individual a) a effective amount of include the nanometer containing taxane (for example, taxol) and carrier protein (for example, albumin) The composition of particle and b) a effective amount of chemotherapeutics.In some embodiments, the melanoma for the treatment of individual human is provided (as shifted Property melanoma, III stages melanoma or IV stages melanoma) method, including give it is individual a) a effective amount of include containing purple The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of the nano particle of China fir alcohol and albumin and b) effectively The chemotherapeutics of amount.
Thus, for example, in some embodiments, providing melanoma (such as metastatic melanoma, III for the treatment of individual human Stage melanoma or IV stages melanoma) method, including give it is individual a) a effective amount of include contain taxol and albumin Nano particle composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) and b) a effective amount of platinum base agent (such as carboplatin or cis-platinum).In some embodiments, provide treatment individual human (include without chemotherapy individual and received before For the individual of the treatment of melanoma) unresectable IV stages melanoma method, including give (such as intravenous administration) Individual a) a effective amount of includes composition (such as Nab- taxols, for example, about of the nano particle containing taxol and albumin 5mg/ml Nab- taxols) and b) a effective amount of carboplatin.In some embodiments, provide treatment individual human (including without change Treatment individual and received before for melanoma treatment individual) unresectable IV stages melanoma method, packet Including and give (such as intravenous administration) individual a) a effective amount of composition for including the nano particle containing taxol and albumin is (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), the dosage of taxol is about wherein in Nanoparticulate compositions 80mg/m2To about 175mg/m2Between (such as from about 100mg/m2To about 150mg/m2Between)；And b) a effective amount of carboplatin.At some In embodiment, it (includes of individual and the treatment for receiving to be directed to melanoma before without chemotherapy to provide treatment individual human Body) unresectable IV stages melanoma method, including give (such as intravenous administration) individual a) it is a effective amount of include contain There is the composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of the nano particle of taxol and albumin, The dosage of taxol is in about 80mg/m in middle Nanoparticulate compositions2To about 175mg/m2Between (such as from about 100mg/m2To about 150mg/m2Between)；And b) a effective amount of carboplatin (for example, carboplatin of AUC2, AUC3, AUC4, AUC5 or AUC6 dosage).One In a little embodiments, Nanoparticulate compositions and carboplatin being given for the 1st, 8,15 day 28 day period.In some embodiments In, Nanoparticulate compositions are given on the the 1st, 8,15 day 28 day period, and carboplatin is given on day 1.In some realities It applies in mode, method further comprises administering to the Sorafenib of individual effective dose (for example, the Suo Lafei of about 400mg daily doses Buddhist nun).In some embodiments, method further comprises administering to the bevacizumab of individual effective dose (for example, about 5mg/kg is to about Between 15mg/kg, such as from about 10mg/kg bevacizumabs).In some embodiments, it is following to further comprise administering to individual for method It is one or more：Temozolomide, proleulzin, interferon (such as Interferon Alpha-2b) and oblimersen.In some embodiments, Individual is without chemotherapy.In some embodiments, received the treatment for melanoma before individual.In some embodiments In, individual is in IV stage melanoma.In some embodiments, individual is in M1c stage melanoma.In some embodiments In, individual includes wild type BRAF.In some embodiments, individual includes that BRAF is mutated (such as BRAF V600E mutation). In some embodiments, individual is male.In some embodiments, individual is women.In some embodiments, individual is At least 65 years old people (including for example, at least 70,75 or 80 years old).In some embodiments, individual is less than 65 years old people (including for example, less than 60,50 or 40 years old).In some embodiments, individual has normal LDH horizontal.In some implementations In mode, individual has raised LDH horizontal.
In some embodiments, melanoma (such as metastatic melanoma, III stage melanoma for the treatment of individual human are provided Or IV stages melanoma) method, including it includes the nano particle containing taxol and albumin to give individual a) a effective amount of Composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) and b) a effective amount of therapeutic antibodies (as anti- VEGF antibody, for example, bevacizumab).In some embodiments, provide treatment individual human (include without chemotherapy individual and Received the individual of the treatment for melanoma before) the III stages or IV stage melanoma method, including give (such as quiet Given in arteries and veins) individual a) it is a effective amount of include the nano particle containing taxol and albumin composition (such as Nab- taxols, For example, about 5mg/ml Nab- taxols) and b) a effective amount of bevacizumab.In some embodiments, treatment individual human is provided The III stages of (including the individual of individual and the treatment for receiving to be directed to melanoma before without chemotherapy) or IV stage melanoma Method, including give the individual a (such as intravenous administration)) it is a effective amount of include the nano particle containing taxol and albumin Composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), the agent of taxol wherein in Nanoparticulate compositions Amount is in about 80mg/m2To about 175mg/m2Between (such as from about 100mg/m2To about 150mg/m2Between)；And b) a effective amount of shellfish cuts down list Anti- (for example, about 5mg/kg to about 15mg/kg, such as from about 10mg/kg bevacizumabs).In some embodiments, method is further Carboplatin including giving individual effective dose.In some embodiments, individual is without chemotherapy.In some embodiments, a Received the treatment for melanoma before body.In some embodiments, individual is in IV stage melanoma.In some implementations In mode, individual is in M1c stage melanoma.In some embodiments, individual includes wild type BRAF.In some embodiment party In formula, individual includes that BRAF is mutated (such as BRAF V600E mutation).In some embodiments, individual is male.In some realities It applies in mode, individual is women.In some embodiments, individual be at least 65 years old people (including for example, at least 70,75 or 80 years old).In some embodiments, individual be less than 65 years old people (including for example, less than 60,50 or 40 years old).In some realities It applies in mode, individual has normal LDH horizontal.In some embodiments, individual has raised LDH horizontal.
In some embodiments, the melanoma for the treatment of individual human (such as the individual with wild type BRAF) is provided (as turned Move property melanoma, III stages melanoma or IV stages melanoma) method, including give (such as intravenous administration) individual a) have Effect amount include the nano particle containing taxol, albumin composition (such as Nab- taxols, for example, about 5mg/ml Nab- Taxol), the dosage of taxol is in about 100mg/m wherein in Nanoparticulate compositions2To about 150mg/m2Between (such as 150mg/ m2)；And b) a effective amount of bevacizumab, wherein the dosage of bevacizumab about 5mg/kg between about 15mg/kg (such as from about 10mg/kg).In some embodiments, the melanoma for the treatment of individual human (such as the individual with wild type BRAF) is provided (as turned Move property melanoma, III stages melanoma or IV stages melanoma) method, including give (such as intravenous administration) individual a) have Effect amount include the nano particle containing taxol, albumin composition (such as Nab- taxols, for example, about 5mg/ml Nab- Taxol), the dosage of taxol is in about 100mg/m wherein in Nanoparticulate compositions2To about 150mg/m2Between (such as 150mg/ m2), wherein Nanoparticulate compositions being given for the 1st, 8,15 day 28 day period；And b) a effective amount of bevacizumab, wherein The dosage of bevacizumab is in about 5mg/kg to (such as from about 10mg/kg) between about 15mg/kg, and wherein bevacizumab was 28 day period It is given within 1st and 15 day.In some embodiments, the unresectable of individual human of the treatment with wild type BRAF is provided The method of IIIc stages or IV stage metastatic melanomas, including it includes containing Japanese yew that intravenous administration individual a) is a effective amount of Alcohol, albumin nano particle composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), wherein nanometer The dosage of taxol is in about 100mg/m in grain composition2To about 150mg/m2Between (such as 150mg/m2), wherein nano particle group Close object being given for the 1st, 8,15 day 28 day period；And b) a effective amount of bevacizumab, wherein the dosage of bevacizumab is about 5mg/kg is to (such as from about 10mg/kg) between about 15mg/kg, wherein bevacizumab being given for the 1st and 15 day 28 day period. In some embodiments, individual is without chemotherapy.In some embodiments, received controlling for melanoma before individual It treats.In some embodiments, individual is in IV stage melanoma.In some embodiments, individual is in M1c stage melanocytes Tumor.In some embodiments, individual includes wild type BRAF.In some embodiments, individual includes that BRAF is mutated (such as BRAF V600E mutation).In some embodiments, individual is male.In some embodiments, individual is women.One In a little embodiments, individual is at least 65 years old people (including for example, at least 70,75 or 80 years old).In some embodiments, Individual be less than 65 years old people (including for example, less than 60,50 or 40 years old).In some embodiments, individual has normal LDH is horizontal.In some embodiments, individual has raised LDH horizontal.
In some embodiments, melanoma (such as metastatic melanoma, III stage melanoma for the treatment of individual human are provided Or IV stages melanoma) method, including it includes the nano particle containing taxol and albumin to give individual a) a effective amount of Composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) and b) a effective amount of Temozolomide.In some realities It applies in mode, treatment individual human (including the individual of individual and the treatment for receiving to be directed to melanoma before without chemotherapy) is provided Metastatic melanoma method, including give (such as intravenous administration) individual a) it is a effective amount of include contain taxol and white egg The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of white nano particle and b) a effective amount of for not azoles Amine.In some embodiments, provide treatment individual human (include without chemotherapy individual and received before be directed to melanoma The individual for the treatment of) metastatic melanoma method, including give (such as intravenous administration) individual a) it is a effective amount of include contain The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of the nano particle of taxol and albumin, wherein The dosage of taxol is in about 80mg/m in Nanoparticulate compositions2To about 175mg/m2Between (such as from about 100mg/m2To about 150mg/ m2Between)；And b) a effective amount of Temozolomide.In some embodiments, method further comprises administering to individual effective dose Oblimersen.In some embodiments, individual is without chemotherapy.In some embodiments, received to be directed to before individual The treatment of melanoma.In some embodiments, individual is in M1c stage melanoma.In some embodiments, individual includes Wild type BRAF.In some embodiments, individual includes that BRAF is mutated (such as BRAF V600E mutation).In some embodiments In, individual is male.In some embodiments, individual is women.In some embodiments, individual is at least 65 years old people (including for example, at least 70,75 or 80 years old).In some embodiments, individual be less than 65 years old people it is (including for example, small In 60,50 or 40 years old).In some embodiments, individual has normal LDH horizontal.In some embodiments, individual tool There is raised LDH horizontal.
In some embodiments, melanoma (such as metastatic melanoma, III stage melanoma for the treatment of individual human are provided Or IV stages melanoma) method, including it includes the nano particle containing taxol and albumin to give individual a) a effective amount of Composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) and b) (such as Sibutramine Hydrochloride replaces a effective amount of mek inhibitor Buddhist nun (GSK1120212)).In some embodiments, provide treatment individual human (include without chemotherapy individual and receive before Cross the individual of the treatment for melanoma) the III stages or IV stage melanoma method, including give (such as intravenous administration) Individual a) a effective amount of includes composition (such as Nab- taxols, for example, about of the nano particle containing taxol and albumin 5mg/ml Nab- taxols) and b) a effective amount of mek inhibitor (such as Trimetinib (GSK1120212)).In some embodiment party In formula, treatment individual human (including the individual of individual and the treatment for receiving to be directed to melanoma before without chemotherapy) is provided The method of III stages or IV stage melanoma, including give (such as intravenous administration) individual a) a effective amount of including containing Japanese yew The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of the nano particle of alcohol and albumin, wherein nanometer The dosage of taxol is in about 80mg/m in particulate composition2To about 175mg/m2Between (such as from about 100mg/m2To about 150mg/m2It Between)；And b) a effective amount of mek inhibitor (such as Trimetinib (GSK1120212)).In some embodiments, individual without Chemotherapy.In some embodiments, received the treatment for melanoma before individual.In some embodiments, at individual In IV stage melanoma.In some embodiments, individual is in M1c stage melanoma.In some embodiments, individual packet Include wild type BRAF.In some embodiments, individual includes that BRAF is mutated (such as BRAF V600E mutation).In some embodiment party In formula, individual is male.In some embodiments, individual is women.In some embodiments, individual is at least 65 years old People (including for example, at least 70,75 or 80 years old).In some embodiments, individual be less than 65 years old people (including for example, Less than 60,50 or 40 years old).In some embodiments, individual has normal LDH horizontal.In some embodiments, individual With raised LDH levels.
In some embodiments, melanoma (such as metastatic melanoma, III stage melanoma for the treatment of individual human are provided Or IV stages melanoma) method, including it includes the nano particle containing taxol and albumin to give individual a) a effective amount of Composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) and b) a effective amount of TH-302.In some implementations In mode, treatment individual human (including the individual of individual and the treatment for receiving to be directed to melanoma before without chemotherapy) is provided The method of III stages or IV stage melanoma, including give (such as intravenous administration) individual a) a effective amount of including containing Japanese yew The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of the nano particle of alcohol and albumin and b) effective quantity TH-302.In some embodiments, treatment individual human is provided (to include individual without chemotherapy and received before for black The individual of the treatment of plain tumor) the III stages or IV stage melanoma method, including give (such as intravenous administration) individual a) have Effect amount include the nano particle containing taxol and albumin composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols), the dosage of taxol is in about 80mg/m wherein in Nanoparticulate compositions2To about 175mg/m2Between (such as from about 100mg/m2To about 150mg/m2Between)；And b) a effective amount of TH-302.In some embodiments, individual is without chemotherapy. In some embodiments, received the treatment for melanoma before individual.In some embodiments, individual is in IV ranks Section melanoma.In some embodiments, individual is in M1c stage melanoma.In some embodiments, individual includes wild Type BRAF.In some embodiments, individual includes that BRAF is mutated (such as BRAF V600E mutation).In some embodiments, Individual is male.In some embodiments, individual is women.In some embodiments, individual is at least 65 years old people (packet It includes, for example, at least 70,75 or 80 years old).In some embodiments, individual is less than 65 years old people and (including for example, is less than 60,50 or 40 years old).In some embodiments, individual has normal LDH horizontal.In some embodiments, individual has Raised LDH is horizontal.
In some embodiments, melanoma (such as metastatic melanoma, III stage melanoma for the treatment of individual human are provided Or IV stages melanoma) method, including it includes the nano particle containing taxol and albumin to give individual a) a effective amount of Composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) and b) a effective amount of oblimersen.In some realities It applies in mode, treatment individual human (including the individual of individual and the treatment for receiving to be directed to melanoma before without chemotherapy) is provided Metastatic melanoma method, including give (such as intravenous administration) individual a) it is a effective amount of include contain taxol and white egg The composition (such as Nab- taxols, for example, about 5mg/ml Nab- taxols) of white nano particle and b) a effective amount of Ao Limo It is gloomy.In some embodiments, provide treatment individual human (include without chemotherapy individual and received before be directed to melanoma The individual for the treatment of) metastatic melanoma method, including give (such as intravenous administration) individual a) it is a effective amount of include contain The composition (such as Nab- taxols, for example, about 5mg/mlNab- taxols) of the nano particle of taxol and albumin, wherein receiving The dosage of taxol is in about 80mg/m in rice grain composition2To about 175mg/m2Between (such as from about 100mg/m2To about 150mg/m2 Between)；And b) a effective amount of oblimersen.In some embodiments, method further comprises administering to replacing for individual effective dose Muzolimine.In some embodiments, individual is without chemotherapy.In some embodiments, received before individual for black The treatment of plain tumor.In some embodiments, individual is in IV stage melanoma.In some embodiments, individual is in M1c Stage melanoma.In some embodiments, individual includes wild type BRAF.In some embodiments, individual includes BRAF It is mutated (such as BRAF V600E mutation).In some embodiments, individual is male.In some embodiments, individual is female Property.In some embodiments, individual is at least 65 years old people (including for example, at least 70,75 or 80 years old).In some implementations In mode, individual be less than 65 years old people (including for example, less than 60,50 or 40 years old).In some embodiments, individual tool There is normal LDH horizontal.In some embodiments, individual has raised LDH horizontal.
In some embodiments, the method for treating melanoma includes any one of the therapeutic regimen that table 4 provides.
4. Nab- taxols of table (or) clinical research
In some embodiments, the method that individual (for example, people) melanoma for the treatment of is provided, including give individual a) effective What is measured includes the composition and b of the nano particle containing taxane (for example, taxol) and carrier protein (for example, albumin)) Operation, radiotherapy or operation and radiotherapy combination.In some embodiments, individual has IV stages or metastatic Melanoma (for example, IV stages or metastatic cutaneous melanoma).In some embodiments, melanoma is the pernicious melanocyte of metastatic Tumor.In some embodiments, metastatic melanoma is in M1a stages, M1b stages or M1c stages.In some embodiments, Metastatic melanoma is in the M1c stages.In some embodiments, melanoma includes the mutation of BRAF.In some embodiments, Melanoma does not include the mutation of BRAF.In some embodiments, melanoma does not include BRAF mutant, and such as activity increases (example Such as, kinase activity increase and/or with wild type BRAF compared with activity increase) BRAF mutant or the enhanced mutation of BRAF functions Body.In some embodiments, melanoma does not include that BRAFV600E is mutated (for example, melanoma includes wild type BRAF).One In a little embodiments, melanoma includes wild type BRAF.In some embodiments, melanoma includes BRAF mutant, such as living Property increase (for example, kinase activity increase and/or with wild type BRAF compared with activity increase) BRAF mutant or BRAF functions Enhanced mutant.In some embodiments, melanoma includes BRAF V600E mutation.In some embodiments, individual With raised Serum LDH level.In some embodiments, individual has about following any Serum LDH：<0.8× ULN、0.4-0.8×ULN、0.8-1.1×ULN、0.9-1.1×ULN、0.8-1.2×ULN、1.1-1.5×ULN、1.2-1.5 × ULN, 1.1-2 × ULN or 1.5-2 × ULN.In some embodiments, individual has the serum less than about 0.8 × ULN LDH.In some embodiments, individual have about 0.8 × to the Serum LDH of about 1.1 × ULN.In some embodiments, a Body has greater than about 1.1 × to the Serum LDH between about 2.0 × ULN.In some embodiments, individual have about 1.1 × extremely Serum LDH between about 2.0 × ULN.In some embodiments, individual is people's (for example, sex).In some implementations In mode, taxane is taxol.In some embodiments, carrier protein is albumin.
In some embodiments, there is the method for the melanoma (such as metastatic melanoma) for the treatment of individual human, including give Individual a) a effective amount of includes the composition of the nano particle containing taxol and albumin and b) a effective amount of bevacizumab. In some embodiments, there is the method for the melanoma (such as metastatic melanoma) for the treatment of individual human, including gives individual a) effective Amount include the nano particle containing taxol and albumin composition and b) a effective amount of bevacizumab, wherein nano particle The dosage of composition is in about 50mg/m2To about 200mg/m2Between (e.g., for example, about 100mg/m2To about 150mg/m2Between, and For example, about 100mg/m2), and wherein bevacizumab dosage about 5mg/kg between about 15mg/kg (e.g., for example, about 8mg/kg is between about 12mg/kg, and for example, about 10mg/kg).In some embodiments, there is the melanoma for the treatment of individual human The method of (such as metastatic melanoma), including it includes the nano particle containing taxol and albumin to give individual a) a effective amount of Composition and b) a effective amount of bevacizumab, wherein the dosage of Nanoparticulate compositions is in about 50mg/m2To about 200mg/m2It Between (e.g., for example, about 100mg/m2To about 150mg/m2Between, and for example, about 100mg/m2), wherein Nanoparticulate compositions Dosage is given on the the 1st, 8 and 15 day 28 day period, wherein the dosage of bevacizumab in about 5mg/kg between about 15mg/kg (e.g., for example, about 8mg/kg is between about 12mg/kg, and for example, about 10mg/kg), and the dosage of wherein bevacizumab is 28 The the 1st and 15 day of its period is given.In some embodiments, there is the melanoma (such as metastatic melanoma) for the treatment of individual human Method, including give it is individual a) a effective amount of include the nano particle containing taxol and albumin composition and b) effectively The dosage of the bevacizumab of amount, wherein Nanoparticulate compositions is about 100mg/m2, and at the 1st, 8 and 15 day of 28 day period By intravenous administration, and the dosage of wherein bevacizumab is about 10mg/kg, and the 1st and 15 day 28 day period is quiet It is given in arteries and veins.In some embodiments, there is the method for the melanoma (such as metastatic melanoma) for the treatment of individual human, including give Individual a) a effective amount of includes the composition of the nano particle containing taxol and albumin and b) a effective amount of bevacizumab, The dosage of middle Nanoparticulate compositions is about 100mg/m2, and the 1st, 8 and 15 day of 28 day period through 30 minutes by vein Inside give, the dosage of wherein bevacizumab is about 10mg/kg, and the 1st and 15 day of 28 day period through 90 minutes by vein Inside give.In some embodiments, individual is without chemotherapy.In some embodiments, received before individual for black The treatment of plain tumor.In some embodiments, individual is in IV stage melanoma.In some embodiments, individual is in M1c Stage melanoma.In some embodiments, individual includes wild type BRAF.In some embodiments, individual includes BRAF It is mutated (such as BRAF V600E mutation).In some embodiments, individual is male.In some embodiments, individual is female Property.In some embodiments, individual is at least 65 years old people (including for example, at least 70,75 or 80 years old).In some implementations In mode, individual be less than 65 years old people (including for example, less than 60,50 or 40 years old).In some embodiments, individual tool There is normal LDH horizontal.In some embodiments, individual has raised LDH horizontal.
In some embodiments, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, including give Individual a) a effective amount of includes the composition of the nano particle containing taxol and albumin and b) a effective amount of BRAF inhibitor. BRAF inhibitor appropriate includes, for example, the non-Buddhist nun of Wella (Zelboraf), GDC-0879, PLX-4720, darafinib (or GSK2118436), LGX 818, CEP-32496, UI-152, RAF 265, Rui Gefeini (BAY 73-4506), CCT239065 Or Sorafenib (or Sorafenib Tosylate or Lei Shawa).In some embodiments, treatment individual human melanocyte is provided The method of tumor (such as metastatic melanoma), including it includes the nanometer containing taxol and albumin to give individual a) a effective amount of The composition of grain, wherein the dosage of Nanoparticulate compositions is in about 50mg/m2To about 200mg/m2Between；And it is b) a effective amount of BRAF inhibitor (e.g., for example, the non-Buddhist nun of Wella (Zelboraf), darafinib, Rui Gefeini or Sorafenib).In some implementations In mode, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, including give and individual a) a effective amount of include The composition of nano particle containing taxol and albumin, wherein the dosage of Nanoparticulate compositions is in about 100mg/m2To about 150mg/m2Between；And b) a effective amount of BRAF inhibitor (e.g., for example, non-Buddhist nun of Wella (Zelboraf)).In some embodiment party In formula, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, including it includes containing to give individual a) a effective amount of There is the composition of the nano particle of taxol and albumin, the dosage of wherein Nanoparticulate compositions is about 100mg/m2；And b) A effective amount of BRAF inhibitor (e.g., for example, the non-Buddhist nun of Wella).In some embodiments, treatment individual human melanoma is provided (such as Metastatic melanoma) method, including it includes the nano particle containing taxol and albumin to give individual a) a effective amount of The dosage of composition, wherein Nanoparticulate compositions is about 100mg/m2, wherein Nanoparticulate compositions 28 day period 1, it is given within 8 and 15 days；And b) a effective amount of BRAF inhibitor (e.g., for example, the non-Buddhist nun of Wella).In some embodiments, it carries For the method for the treatment of individual human melanoma (such as metastatic melanoma), including it includes containing taxol to give individual a) a effective amount of Dosage with the composition of the nano particle of albumin, wherein Nanoparticulate compositions is about 100mg/m2, wherein nano particle Composition the 1st, 8 and 15 day of 28 day period through 30 minutes by intravenous administration；And b) a effective amount of BRAF inhibitor is (e.g., For example, the non-Buddhist nun of Wella).In some embodiments, individual is without chemotherapy.In some embodiments, receive before individual Cross the treatment for melanoma.In some embodiments, individual is in IV stage melanoma.In some embodiments, a Body is in M1c stage melanoma.In some embodiments, individual includes wild type BRAF.In some embodiments, individual It is mutated (such as BRAF V600E mutation) including BRAF.In some embodiments, individual is male.In some embodiments, Individual is women.In some embodiments, individual is at least 65 years old people (including for example, at least 70,75 or 80 years old). In some embodiments, individual be less than 65 years old people (including for example, less than 60,50 or 40 years old).In some embodiments In, individual has normal LDH horizontal.In some embodiments, individual has raised LDH horizontal.
In some embodiments, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, including give Individual a) a effective amount of includes the composition of the nano particle containing taxol and albumin and b) other a effective amount of chemotherapeutics, Wherein received before individual using at least one BRAF inhibitor (e.g., for example, the non-Buddhist nun of Wella (Zelboraf) or Suo Lafei Buddhist nun) the treatment for melanoma, and wherein individual substantially it is refractory in preceding BRAF inhibitor for treating.In some implementations In mode, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, including give and individual a) a effective amount of include The composition of nano particle containing taxol and albumin, wherein the dosage of Nanoparticulate compositions is in about 50mg/m2To about 200mg/m2Between；And b) other a effective amount of chemotherapeutics, wherein receiving to utilize at least one BRAF inhibitor before individual The treatment for melanoma of (e.g., for example, the non-Buddhist nun of Wella (Zelboraf) or Sorafenib), and wherein individual is substantially It is refractory in preceding BRAF inhibitor for treating.In some embodiments, treatment individual human melanoma (such as metastatic melanocyte is provided Tumor) method, including give it is individual a) a effective amount of include the nano particle containing taxol and albumin composition, wherein The dosage of Nanoparticulate compositions is in about 100mg/m2To about 150mg/m2Between；And b) other a effective amount of chemotherapeutics, wherein a Received the needle using at least one BRAF inhibitor (e.g., for example, the non-Buddhist nun of Wella (Zelboraf) or Sorafenib) before body Treatment to melanoma, and wherein individual is substantially refractory in preceding BRAF inhibitor for treating.In some embodiments, The method that treatment individual human melanoma (such as metastatic melanoma) is provided, including it includes containing Japanese yew to give individual a) a effective amount of The dosage of the composition of the nano particle of alcohol and albumin, wherein Nanoparticulate compositions is about 100mg/m2And b) effective quantity Other chemotherapeutics, wherein individual before received using at least one BRAF inhibitor (e.g., for example, the non-Buddhist nun of Wella (Zelboraf) or Sorafenib) the treatment for melanoma, and wherein individual substantially controlled in preceding BRAF inhibitor It treats refractory.In some embodiments, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, including give Individual a) a effective amount of includes the composition of the nano particle containing taxol and albumin, the wherein agent of Nanoparticulate compositions Amount is about 100mg/m2, wherein Nanoparticulate compositions being given for the 1st, 8 and 15 day 28 day period；And b) it is a effective amount of its His chemotherapeutics, wherein receiving before individual using at least one BRAF inhibitor (e.g., for example, the non-Buddhist nun of Wella (Zelboraf) Or Sorafenib) the treatment for melanoma, and wherein individual substantially it is refractory in preceding BRAF inhibitor for treating. In some embodiments, individual is in IV stage melanoma.In some embodiments, individual is in M1c stage melanoma. In some embodiments, individual includes wild type BRAF.In some embodiments, individual includes that BRAF is mutated (such as BRAF V600E is mutated).In some embodiments, individual is male.In some embodiments, individual is women.In some implementations In mode, individual is at least 65 years old people (including for example, at least 70,75 or 80 years old).In some embodiments, individual is Less than 65 years old people (including for example, less than 60,50 or 40 years old).In some embodiments, individual has normal LDH water It is flat.In some embodiments, individual has raised LDH horizontal.
In some embodiments, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, including give Individual effective dose includes the composition of the nano particle containing taxol and albumin, wherein receiving before individual using extremely A kind of few treatment for melanoma of BRAF inhibitor (e.g., for example, the non-Buddhist nun of Wella (Zelboraf) or Sorafenib), and Wherein individual is substantially refractory in preceding BRAF inhibitor for treating.In some embodiments, treatment individual human melanocyte is provided The method of tumor (such as metastatic melanoma), including give individual effective dose includes the nano particle containing taxol and albumin Composition, wherein the dosage of Nanoparticulate compositions is in about 50mg/m2To about 200mg/m2Between, wherein receiving before individual It crosses and is directed to melanoma using at least one BRAF inhibitor (e.g., for example, the non-Buddhist nun of Wella (Zelboraf) or Sorafenib) Treatment, and wherein individual is substantially refractory in preceding BRAF inhibitor for treating.In some embodiments, treatment people is provided The method of a autologous melanoma (such as metastatic melanoma), including give individual effective dose includes containing taxol and albumin The composition of nano particle, wherein the dosage of Nanoparticulate compositions is in about 100mg/m2To about 150mg/m2Between, wherein individual Received being directed to using at least one BRAF inhibitor (e.g., for example, the non-Buddhist nun of Wella (Zelboraf) or Sorafenib) before The treatment of melanoma, and wherein individual is substantially refractory in preceding BRAF inhibitor for treating.In some embodiments, it carries For the method for the treatment of individual human melanoma (such as metastatic melanoma), including give individual effective dose include containing taxol and The dosage of the composition of the nano particle of albumin, wherein Nanoparticulate compositions is about 100mg/m2, wherein being connect before individual It has received and has been directed to melanoma using at least one BRAF inhibitor (e.g., for example, the non-Buddhist nun of Wella (Zelboraf) or Sorafenib) Treatment, and wherein individual substantially it is refractory in preceding BRAF inhibitor for treating.In some embodiments, treatment is provided The method of individual human melanoma (such as metastatic melanoma), including give individual effective dose includes containing taxol and albumin Nano particle composition, the dosage of wherein Nanoparticulate compositions is about 100mg/m2, wherein Nanoparticulate compositions exist The the 1st, 8 and 15 day of 28 day period is given, wherein received before individual using at least one BRAF inhibitor (e.g., for example, The non-Buddhist nun of Wella (Zelboraf) or Sorafenib) the treatment for melanoma, and wherein individual substantially in preceding BRAF Inhibitor for treating is refractory.In some embodiments, individual is in IV stage melanoma.In some embodiments, individual In M1c stage melanoma.In some embodiments, individual includes wild type BRAF.In some embodiments, individual packet Include BRAF mutation (such as BRAF V600E mutation).In some embodiments, individual is male.In some embodiments, a Body is women.In some embodiments, individual is at least 65 years old people (including for example, at least 70,75 or 80 years old).One In a little embodiments, individual be less than 65 years old people (including for example, less than 60,50 or 40 years old).In some embodiments, Individual has normal LDH horizontal.In some embodiments, individual has raised LDH horizontal.
In some embodiments, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, including give Individual a) a effective amount of includes the composition of the nano particle containing taxol and albumin；And b) her a effective amount of wood is single It is anti-.In some embodiments, provide treatment individual human melanoma (such as metastatic melanoma) method, including give it is individual a) A effective amount of includes the composition of the nano particle containing taxol and albumin, and wherein the dosage of Nanoparticulate compositions is about 50mg/m2To about 200mg/m2Between；And b) her a effective amount of wooden monoclonal antibody, wherein the dosage of her the wooden monoclonal antibody is in about 1mg/kg To between about 5mg/kg.In some embodiments, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, packet Include give it is individual a) a effective amount of include the nano particle containing taxol and albumin composition, wherein nano particle combine The dosage of object is in about 100mg/m2To about 150mg/m2Between；And b) her a effective amount of wooden monoclonal antibody, the wherein agent of her the wooden monoclonal antibody Amount is in about 2mg/kg between about 4mg/kg.In some embodiments, treatment individual human melanoma (such as metastatic melanocyte is provided Tumor) method, including give it is individual a) a effective amount of include the nano particle containing taxol and albumin composition, wherein The dosage of Nanoparticulate compositions is about 100mg/m2；And b) her a effective amount of wooden monoclonal antibody, the wherein dosage of her the wooden monoclonal antibody It is about 3mg/kg.In some embodiments, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, including give Give it is individual a) a effective amount of include nano particle containing taxol and albumin composition, wherein Nanoparticulate compositions Dosage is about 100mg/m2, wherein Nanoparticulate compositions being given for the 1st, 8 and 15 day 28 day period；And it is b) a effective amount of Her wooden monoclonal antibody, wherein her dosage of the wooden monoclonal antibody is about 3mg/kg, and wherein the 1st day 21 day period of her wooden monoclonal antibody It is given.In some embodiments, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, including give a Body a) is a effective amount of include the nano particle containing taxol and albumin composition, the wherein dosage of Nanoparticulate compositions It is about 100mg/m2, wherein Nanoparticulate compositions the 1st, 8 and 15 day of 28 day period through 30 minutes by intravenous administration；With B) her a effective amount of wooden monoclonal antibody, wherein her dosage of the wooden monoclonal antibody is about 3mg/kg, and wherein her wooden monoclonal antibody was 21 day period The 1st day through 30 minutes by intravenous administration.In some embodiments, individual is without chemotherapy.In some embodiments, Received the treatment for melanoma before individual.In some embodiments, individual is in IV stage melanoma.In some realities It applies in mode, individual is in M1c stage melanoma.In some embodiments, individual includes wild type BRAF.In some implementations In mode, individual includes that BRAF is mutated (such as BRAF V600E mutation).In some embodiments, individual is male.At some In embodiment, individual is women.In some embodiments, individual is at least 65 years old people (including for example, at least 70,75 Or 80 years old).In some embodiments, individual be less than 65 years old people (including for example, less than 60,50 or 40 years old).At some In embodiment, individual has normal LDH horizontal.In some embodiments, individual has raised LDH horizontal.
In some embodiments, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, including give Individual a) a effective amount of includes the composition of the nano particle containing taxol and albumin；And b) a effective amount of anti-PD-1 is anti- Body.In some embodiments, provide treatment individual human melanoma (such as metastatic melanoma) method, including give it is individual a) A effective amount of includes the composition of the nano particle containing taxol and albumin, and wherein the dosage of Nanoparticulate compositions is about 50mg/m2To about 200mg/m2Between (e.g., for example, about 100mg/m2About 150mg/m2Between, for example, about 100mg/m2)；With B) a effective amount of anti-PD-1 antibody, the dosage of moderate resistance PD-1 antibody about 0.1mg/kg between about 15mg/kg (e.g., for example, About 2mg/kg is between about 12mg/kg, for example, about 10mg/kg).In some embodiments, treatment individual human melanoma is provided The method of (such as metastatic melanoma), including it includes the nano particle containing taxol and albumin to give individual a) a effective amount of Composition, the dosage of wherein Nanoparticulate compositions is about 100mg/m2；And b) a effective amount of anti-PD-1 antibody, moderate resistance The dosage of PD-1 antibody is about 10mg/kg.In some embodiments, individual is without chemotherapy.In some embodiments, a Received the treatment for melanoma before body.In some embodiments, individual is in IV stage melanoma.In some implementations In mode, individual is in M1c stage melanoma.In some embodiments, individual includes wild type BRAF.In some embodiment party In formula, individual includes that BRAF is mutated (such as BRAF V600E mutation).In some embodiments, individual is male.In some realities It applies in mode, individual is women.In some embodiments, individual be at least 65 years old people (including for example, at least 70,75 or 80 years old).In some embodiments, individual be less than 65 years old people (including for example, less than 60,50 or 40 years old).In some realities It applies in mode, individual has normal LDH horizontal.In some embodiments, individual has raised LDH horizontal.
In some embodiments, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, including give Individual a) a effective amount of includes the composition of the nano particle containing taxol and albumin and b) a effective amount of anti-PD-L1 is anti- Body.In some embodiments, provide treatment individual human melanoma (such as metastatic melanoma) method, including give it is individual a) A effective amount of includes the composition of the nano particle containing taxol and albumin, and wherein the dosage of Nanoparticulate compositions is about 50mg/m2To about 200mg/m2Between (e.g., for example, about 100mg/m2About 150mg/m2Between, for example, about 100mg/m2)；With B) a effective amount of anti-PD-L1 antibody, the dosage of moderate resistance PD-L1 antibody is in about 0.3mg/kg to (e.g., example between about 15mg/kg Such as, about 2mg/kg is between about 12mg/kg, for example, about 10mg/kg).In some embodiments, it is black to provide treatment individual human The method of plain tumor (such as metastatic melanoma), including it includes the nanometer containing taxol and albumin to give individual a) a effective amount of The dosage of the composition of particle, wherein Nanoparticulate compositions is about 100mg/m2；And b) a effective amount of anti-PD-L1 antibody, The dosage of moderate resistance PD-L1 antibody is about 10mg/kg.In some embodiments, individual is without chemotherapy.In some embodiments In, received the treatment for melanoma before individual.In some embodiments, individual is in IV stage melanoma.One In a little embodiments, individual is in M1c stage melanoma.In some embodiments, individual includes wild type BRAF.At some In embodiment, individual includes that BRAF is mutated (such as BRAF V600E mutation).In some embodiments, individual is male. In some embodiments, individual is women.In some embodiments, individual be at least 65 years old people (including for example, at least 70,75 or 80 years old).In some embodiments, individual be less than 65 years old people (including for example, less than 60,50 or 40 years old). In some embodiments, individual has normal LDH horizontal.In some embodiments, individual has raised LDH water It is flat.
In some embodiments, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, including give Individual a) a effective amount of includes the composition of the nano particle containing taxol and albumin, b) a effective amount of her wooden monoclonal antibody, And c) a effective amount of bevacizumab.In some embodiments, treatment individual human melanoma (such as metastatic melanoma) is provided Method, including give individual a) a effective amount of composition for including the nano particle containing taxol and albumin, b) effective quantity Her wooden monoclonal antibody and c) a effective amount of bevacizumab, wherein the dosage of Nanoparticulate compositions is in about 50mg/m2To about 200mg/m2Between, wherein the dosage of her the wooden monoclonal antibody in about 1mg/kg between about 5mg/kg, and wherein bevacizumab Dosage is in about 5mg/kg between 15mg/kg.In some embodiments, providing treatment individual human melanoma, (such as metastatic is black Plain tumor) method, including give it is individual a) a effective amount of include the nano particle containing taxol and albumin composition, b) Her a effective amount of wooden monoclonal antibody and c) a effective amount of bevacizumab, wherein the dosage of Nanoparticulate compositions is in about 100mg/m2Extremely About 150mg/m2Between, wherein the dosage of her the wooden monoclonal antibody in about 2mg/kg between about 4mg/kg, and wherein bevacizumab Dosage in about 8mg/kg between 12mg/kg.In some embodiments, treatment individual human melanoma (such as metastatic is provided Melanoma) method, including give it is individual a) a effective amount of include the nano particle containing taxol and albumin composition, B) her a effective amount of wooden monoclonal antibody and c) a effective amount of bevacizumab, the dosage of wherein Nanoparticulate compositions is about 100mg/ m2, wherein her dosage of the wooden monoclonal antibody is about 3mg/kg, and the dosage of wherein bevacizumab is about 10mg/kg.In some realities It applies in mode, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, including gives individual a) a effective amount of packet Composition, b) her a effective amount of wooden monoclonal antibody and c) a effective amount of shellfish cuts down list for including the nano particle containing taxol and albumin Anti-, the dosage of wherein Nanoparticulate compositions is about 100mg/m2, and the 1st, 8 and 15 day 28 day period is given, In her dosage of the wooden monoclonal antibody be about 3mg/kg, and the 1st day 21 day period is given, and the agent of wherein bevacizumab Amount is about 10mg/kg, and the 1st and 15 day 28 day period is given.In some embodiments, treatment individual human is provided The method of melanoma (such as metastatic melanoma), including it includes receiving containing taxol and albumin to give individual a) a effective amount of The composition of rice grain, b) her a effective amount of wooden monoclonal antibody and c) a effective amount of bevacizumab, wherein Nanoparticulate compositions Dosage is about 100mg/m2, and at the 1st, 8 and 15 day of 28 day period by intravenous administration, the wherein dosage of her the wooden monoclonal antibody It is about 3mg/kg, and at the 1st day of 21 day period and by intravenous administration, and the dosage of wherein bevacizumab is about 10mg/kg, and at the 1st and 15 day of 28 day period by intravenous administration.In some embodiments, individual is without change It treats.In some embodiments, received the treatment for melanoma before individual.In some embodiments, individual is in IV stage melanoma.In some embodiments, individual is in M1c stage melanoma.In some embodiments, individual includes Wild type BRAF.In some embodiments, individual includes that BRAF is mutated (such as BRAF V600E mutation).In some embodiments In, individual is male.In some embodiments, individual is women.In some embodiments, individual is at least 65 years old people (including for example, at least 70,75 or 80 years old).In some embodiments, individual be less than 65 years old people it is (including for example, small In 60,50 or 40 years old).In some embodiments, individual has normal LDH horizontal.In some embodiments, individual tool There is raised LDH horizontal.
In some embodiments, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, including give It is individual a) a effective amount of include the nano particle containing taxol and albumin composition, b) her a effective amount of wooden monoclonal antibody, C) a effective amount of bevacizumab and d) a effective amount of Temozolomide.In some embodiments, treatment individual human melanoma is provided The method of (such as metastatic melanoma), including it includes the nano particle containing taxol and albumin to give individual a) a effective amount of Composition, b) her a effective amount of wooden monoclonal antibody, c) a effective amount of bevacizumab and d) a effective amount of Temozolomide, wherein nanometer The dosage of particulate composition is in about 50mg/m2To about 200mg/m2Between, (e.g., for example, about 100mg/m2To about 150mg/m2It Between, and for example, about 100mg/m2), wherein the dosage of her the wooden monoclonal antibody in about 1mg/kg between about 5mg/kg, (e.g., for example, About 2mg/kg is between about 4mg/kg, and for example, about 3mg/kg), wherein the dosage of bevacizumab is in about 5mg/kg to 15mg/kg Between (e.g., for example, between about 7mg/kg and 12mg/kg, and for example, about 10mg/kg), and the dosage of wherein Temozolomide exists About 25mg/m2And 125mg/m2Between, (e.g., for example, about 50mg/m2To about 100mg/m2Between, and for example, about 75mg/m2). In some embodiments, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, including give individual a) effective The composition for including the nano particle containing taxol and albumin, b) her a effective amount of wooden monoclonal antibody, c) a effective amount of of amount The dosage of bevacizumab and d) a effective amount of Temozolomide, wherein Nanoparticulate compositions is about 100mg/m2, wherein her wood The dosage of monoclonal antibody is about 3mg/kg, and the dosage of wherein bevacizumab is about 10mg/kg, and the dosage of wherein Temozolomide is about 75mg/m2.In some embodiments, the method that treatment individual human melanoma (such as metastatic melanoma) is provided, including give It is individual a) a effective amount of include the nano particle containing taxol and albumin composition, b) her a effective amount of wooden monoclonal antibody, C) dosage of a effective amount of bevacizumab and d) a effective amount of Temozolomide, wherein Nanoparticulate compositions is about 100mg/m2, And the 1st, 8 and 15 day 28 day period is given, and wherein her dosage of the wooden monoclonal antibody was about 3mg/kg, and 21 day week The 1st day of phase is given, and the dosage of wherein bevacizumab is about 10mg/kg, and the 1st and 15 day of 28 day period by It gives, and the dosage of wherein Temozolomide is about 75mg/m2, and be given at the 1st to 42 day.In some embodiments, The method that treatment individual human melanoma (such as metastatic melanoma) is provided, including it includes containing Japanese yew to give individual a) a effective amount of The composition of the nano particle of alcohol and albumin, b) her a effective amount of wooden monoclonal antibody, c) a effective amount of bevacizumab and d) effectively The dosage of the Temozolomide of amount, wherein Nanoparticulate compositions is about 100mg/m2, and at the 1st, 8 and 15 day of 28 day period By intravenous administration, wherein her dosage of the wooden monoclonal antibody is about 3mg/kg, and is given at the 1st day of 21 day period and intravenously It giving, the dosage of wherein bevacizumab is about 10mg/kg, and at the 1st and 15 day of 28 day period by intravenous administration, and its The dosage of middle Temozolomide is about 75mg/m2, and be given at the 1st to 42 day.In some embodiments, individual without Chemotherapy.In some embodiments, received the treatment for melanoma before individual.In some embodiments, at individual In IV stage melanoma.In some embodiments, individual is in M1c stage melanoma.In some embodiments, individual packet Include wild type BRAF.In some embodiments, individual includes that BRAF is mutated (such as BRAF V600E mutation).In some embodiment party In formula, individual is male.In some embodiments, individual is women.In some embodiments, individual is at least 65 years old People (including for example, at least 70,75 or 80 years old).In some embodiments, individual be less than 65 years old people (including for example, Less than 60,50 or 40 years old).In some embodiments, individual has normal LDH horizontal.In some embodiments, individual With raised LDH levels.
In some embodiments, individual has IV stages or metastatic melanoma (for example, IV stages or metastatic skin Melanoma).In some embodiments, melanoma is metastatic malignant melanoma.In some embodiments, metastatic melanocyte Tumor is in M1a stages, M1b stages or M1c stages.In some embodiments, metastatic melanoma is in the M1c stages.In some realities It applies in mode, melanoma includes the mutation of BRAF.In some embodiments, melanoma includes one kind in following BRAF mutation Or it is a variety of：R461I、I462S、G463E、G463V、G465A、G465E、G465V、G468A、G468E、N580S、E585K、 D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, K600E or A727V.In some implementations In mode, melanoma does not include the mutation of BRAF.In some embodiments, melanoma includes BRAF mutant, and such as activity increases Add the BRAF mutant or the enhancing of BRAF functions of (for example, kinase activity increases and/or activity increases compared with wild type BRAF) Type mutant.In some embodiments, melanoma does not include BRAF mutant, and such as activity increases (for example, kinase activity increases And/or compared with wild type BRAF activity increase) BRAF mutant or the enhanced mutant of BRAF functions.In some embodiment party In formula, melanoma includes BRAF mutant, and such as activity is reduced (for example, kinase activity is reduced and/or lived compared with wild type BRAF Property reduce) BRAF mutant or BRAF miopragia type mutant.In some embodiments, melanoma includes that composing type is lived Property BRAF.In some embodiments, melanoma does not include constitutive activity BRAF.In some embodiments, melanoma packet Include BRAF V600E mutation.In some embodiments, melanoma does not include BRAF V600E mutation (for example, melanoma includes Wild type BRAF).In some embodiments, melanoma includes wild type BRAF.
Administration route
The taxane Nanoparticulate compositions dosage for giving individual (such as people) can be with concrete composition, administration route and this paper The treated melanoma type and change.The taxane Nanoparticulate compositions dosage for giving individual (such as people) may be based on Individual symptom (such as adverse reaction) adjusts (as reduce).In some embodiments, amount of composition effectively generates response.One In a little embodiments, amount of composition effectively generates objective response (such as part response or complete response).In some embodiments, The administered dose (for example, when individually giving) of taxane Nanoparticulate compositions is enough to treat in taxane Nanoparticulate compositions Groups of individuals in generate greater than about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, any of 75%, 80%, 85% or 90% Whole Response rate.Individual can to the response of therapy described herein It is determined with methods known in the art.
In some embodiments, amount of composition is enough to extend the progression free survival phase of individual.In some embodiments, Amount of composition is enough to extend the life cycle of individual.In some embodiments, amount of composition is enough to improve the quality of life of individual. In some embodiments, amount of composition while giving (for example, individually) is enough to treat in taxane Nanoparticulate compositions Greater than about any of 50%, 60%, 70% or 77% clinical benefit is generated in groups of individuals.
In some embodiments, the amount of composition, the first therapy, the second therapy or combination treatment is to be enough to make melanoma Size reduction, make melanoma cells quantity reduce or make melanoma growth rate reduce at least about 10%, 20%, 30%, 40%, 50%, any of 60%, 70%, 80%, 90%, 95% or 100% amount --- it swells to the corresponding of same individual before treatment Tumor size, melanoma cells quantity or tumor growth rate compare or to the corresponding active phases for other individuals for not receiving treatment Than.The method that can be used for measuring the magnitude of this effect is known in the art.
In some embodiments, the taxane in composition (for example, taxol) amount cause toxicological effect (that is, facing The effect more than acceptable toxic level of bed) it is below horizontal, or in the potential side effect when composition is given individual Controllable or tolerable level.
In some embodiments, maximum tolerated dose of the amount of composition close to the composition for following same medicine scheme (MTD).In some embodiments, amount of composition is more than any of about 80%, 90%, 95% or 98% of MTD.
In some embodiments, taxane (for example, taxol) amount (dosage) the opinion row in office that composition includes In range：About 0.1mg to about 500mg, about 0.1mg are to about 2.5mg, about 0.5 to about 5mg, about 5 to about 10mg, about 10 to about 15mg, about 15 to about 20mg, about 20 to about 25mg, about 20 to about 50mg, about 25 to about 50mg, about 50 to about 75mg, about 50 to About 100mg, about 75 to about 100mg, about 100 to about 125mg, about 125 to about 150mg, about 150 to about 175mg, about 175 are to about 200mg, about 200 to about 225mg, about 225 to about 250mg, about 250 to about 300mg, about 300 to about 350mg, about 350 are to about 400mg, about 400 to about 450mg or about 450 to about 500mg.In some embodiments, a effective amount of composition is (for example, single Position dosage form) in taxane (for example, taxol) amount (dosage) within the scope of the following：About 5mg to about 500mg, such as from about 30mg extremely About 300mg or about 50mg are to about 200mg.In some embodiments, the concentration of taxane (for example, taxol) in the composition It is dilute (about 0.1mg/ml) or dense (about 100mg/ml), including, for example, about 0.1 to about 50mg/ml, about 0.1 to about 20mg/ml, about 1 to about 10mg/ml, about 2mg/ml to about 8mg/ml, about 4 to about 6mg/ml or about any of 5mg/ml. In some embodiments, the concentration of taxane (for example, taxol) be at least about 0.5mg/ml, 1.3mg/ml, 1.5mg/ml, 2mg/ml、3mg/ml、4mg/ml、5mg/ml、6mg/ml、7mg/ml、8mg/ml、9mg/ml、10mg/ml、15mg/ml、20mg/ Any of ml, 25mg/ml, 30mg/ml, 40mg/ml or 50mg/ml.In some embodiments, taxane is (for example, purple China fir alcohol) concentration no more than about 100mg/ml, 90mg/ml, 80mg/ml, 70mg/ml, 60mg/ml, 50mg/ml, 40mg/ml, Any of 30mg/ml, 20mg/ml, 10mg/ml or 5mg/ml.
Exemplary taxane (for example, taxol) in Nanoparticulate compositions measures (dosage), at least About 25mg/m2、30mg/m2、50mg/m2、60mg/m2、75mg/m2、80mg/m2、90mg/m2、100mg/m2、120mg/m2、 125mg/m2、150mg/m2、160mg/m2、175mg/m2、180mg/m2、200mg/m2、210mg/m2、220mg/m2、250mg/ m2、260mg/m2、300mg/m2、350mg/m2、400mg/m2、500mg/m2、540mg/m2、750mg/m2、1000mg/m2Or 1080mg/m2Any of taxane (for example, taxol).In different embodiments, composition includes being less than about 350mg/m2、300mg/m2、250mg/m2、200mg/m2、150mg/m2、120mg/m2、100mg/m2、90mg/m2、50mg/m2Or 30mg/m2Any of taxane (for example, taxol).In some embodiments, give every time taxane (for example, Taxol) it measures less than about 25mg/m2、22mg/m2、20mg/m2、18mg/m2、15mg/m2、14mg/m2、13mg/m2、12mg/m2、 11mg/m2、10mg/m2、9mg/m2、8mg/m2、7mg/m2、6mg/m2、5mg/m2、4mg/m2、3mg/m2、2mg/m2Or 1mg/m2In Either one or two of.In some embodiments, taxane (for example, taxol) amount (dosage) the opinion row in office that composition includes In range：About 1 to about 5mg/m2, about 5 to about 10mg/m2, about 10 to about 25mg/m2, about 25 to about 50mg/m2, about 50 to about 75mg/m2, about 75 to about 100mg/m2, about 100 to about 125mg/m2, about 100 to about 200mg/m2, about 125 to about 150mg/m2、 About 125 to about 175mg/m2, about 150 to about 175mg/m2, about 175 to about 200mg/m2, about 200 to about 225mg/m2, about 225 To about 250mg/m2, about 250 to about 300mg/m2, about 300 to about 350mg/m2Or about 350 to about 400mg/m2.In some implementations In mode, within the scope of taxane (for example, taxol) amount (dosage) opinion row in office that composition includes：About 10mg/m2Extremely About 400mg/m2, about 25mg/m2To about 400mg/m2, about 50mg/m2To about 400mg/m2, about 75mg/m2To about 350mg/m2, about 75mg/m2To about 300mg/m2, about 75mg/m2To about 250mg/m2, about 75mg/m2To about 200mg/m2, about 75mg/m2To about 150mg/m2, about 75mg/m2To about 125mg/m2, about 100mg/m2To about 260mg/m2, about 100mg/m2To about 250mg/m2, about 100mg/m2To about 200mg/m2Or about 125mg/m2To about 175mg/m2.In some embodiments, the taxane in composition It is about 5 to about 300mg/m that (for example, taxol), which measures (dosage),2, about 100 to about 200mg/m2, about 100 to about 150mg/m2, about 50 to about 150mg/m2, about 75 to about 150mg/m2, about 75 to about 125mg/m2Or about 70mg/m2, about 80mg/m2, about 90mg/ m2, about 100mg/m2, about 110mg/m2, about 120mg/m2, about 130mg/m2, about 140mg/m2, about 150mg/m2, about 160mg/m2、 About 170mg/m2, about 180mg/m2, about 190mg/m2, about 200mg/m2, about 250mg/m2, about 260mg/m2Or about 300mg/m2。
In some embodiments of any of the above-described aspect, taxane (for example, taxol) amount (dosage) in composition Including at least about 1mg/kg, 2.5mg/kg, 3.5mg/kg, 5mg/kg, 6.5mg/kg, 7.5mg/kg, 10mg/kg, 15mg/kg, In 20mg/kg, 25mg/kg, 30mg/kg, 35mg/kg, 40mg/kg, 45mg/kg, 50mg/kg, 55mg/kg or 60mg/kg Any one.In different embodiments, the taxane in composition (for example, taxol) amount (dosage) includes being less than about 350mg/ kg、300mg/kg、250mg/kg、200mg/kg、150mg/kg、100mg/kg、50mg/kg、25mg/kg、20mg/kg、10mg/ The taxane of any of kg, 7.5mg/kg, 6.5mg/kg, 5mg/kg, 3.5mg/kg, 2.5mg/kg or 1mg/kg are (for example, purple China fir alcohol).
The exemplary medicine frequency for giving Nanoparticulate compositions includes but not limited to, daily, every two days, every three days, often Four days, it is five days every, six days every, weekly three weeks in uninterrupted, surrounding weekly, once every three weeks, once every two weeks or in three weeks Two weeks.In some embodiments, give composition about once every 2 weeks, every 3 weeks primary, every 6 weeks primary, every 4 weeks it is primary or Every 8 weeks primary.In some embodiments, give composition one week at least about 1 ×, 2 ×, 3 ×, 4 ×, 5 ×, 6 × or 7 × Any one of (i.e., daily).In some embodiments, the interval between giving every time is less than about 6 months, 3 months, 1 Month, 20 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or in 1 day Either one or two of.In some embodiments, the interval between giving every time is greater than about 1 month, 2 months, 3 months, 4 months, 5 Either one or two of the moon, 6 months, 8 months or 12 middle of the month.In some embodiments, free of discontinuities in medication schedule.In some implementations In mode, the interval between giving every time is not greater than about one week.
In some embodiments, medicine frequency be once every two days, totally one time, twice, three times, four times, five times, six All over, seven times, eight times, nine times, ten times and 11 times.In some embodiments, medicine frequency is totally five times once every two days. In some embodiments, taxane (for example, taxol) at least ten day time is given, wherein the interval between giving every time is not Greater than about two days, and taxane (for example, taxol) dosage wherein given every time is about 0.25mg/m2To about 250mg/m2、 About 0.25mg/m2To about 150mg/m2, about 0.25mg/m2To about 75mg/m2, such as from about 0.25mg/m2To about 25mg/m2, about 25mg/ m2To about 50mg/m2Or about 50mg/m2To about 100mg/m2。
Giving for composition can continue for a long time, and such as from about one month up to about seven years.In some embodiments, it gives and combines The time of any of object at least about 2,3,4,5,6,7,8,9,10,11,12,18,24,30,36,48,60,72 or 84 months.
In some embodiments, dosage of the taxane (for example, taxol) in Nanoparticulate compositions can be under Within the scope of row：5-400mg/m when arranging to give based on 3 weeks2Or based on 5-250mg/m when arranging to give weekly2(such as 75-200mg/ m2, 100-200mg/m2, for example, 125-175mg/m2).For example, taxane (for example, taxol) amount arranged based on three weeks is About 60 to about 300mg/m2(for example, about 100mg/m2、125mg/m2、150mg/m2、175mg/m2、200mg/m2、225mg/m2、 250mg/m2Or 260mg/m2).In some embodiments, taxane (for example, taxol) amount when giving weekly be about 60 to About 300mg/m2(for example, about 100mg/m2、125mg/m2、150mg/m2、175mg/m2、200mg/m2、225mg/m2、250mg/m2 Or 260mg/m2).In some embodiments, taxane (for example, taxol) amount was given weekly based on arrangement in three weeks in surrounding It is about 60 to about 300mg/m when giving2(for example, about 100mg/m2、125mg/m2、150mg/m2、175mg/m2、200mg/m2、 225mg/m2、250mg/m2Or 260mg/m2)。
Give other exemplary medications of Nanoparticulate compositions (for example, taxol/albumin nanoparticle composition) Arrangement includes but not limited to 100mg/m2, weekly, free of discontinuities；75mg/m2, weekly, three weeks in surrounding；100mg/m2, weekly, Three weeks in surrounding；125mg/m2, weekly, three weeks in surrounding；150mg/m2, weekly, three weeks in surrounding；175mg/m2, often Week, three weeks in surrounding；125mg/m2, weekly, 2 weeks in 3 weeks；130mg/m2, weekly, free of discontinuities；175mg/m2, every 2 weeks one It is secondary；260mg/m2, once every 2 weeks；260mg/m2, every 3 weeks once；180-300mg/m2, every three weeks；60-175mg/m2, weekly, It is free of discontinuities；20-150mg/m2, biweekly；And 150-250mg/m2, biweekly.The medicine frequency of composition can be in treatment phase Between adjusted based on the judgement of administration doctor.
In some embodiments, appointing in individual at least about 1,2,3,4,5,6,7,8,9 or 10 treatment cycle is treated One.
Composition as described herein allows composition being perfused to individual through shorter than about 24 hours infusion times.For example, In some embodiments, composition pass through less than about 24 hours, 12 hours, 8 hours, 5 hours, 3 hours, 2 hours, 1 hour, 30 The infusion time of any of minute, 20 minutes or 10 minutes are given.In some embodiments, composition was through about 30 minutes Infusion time be given.
Other exemplary doses of taxane (in some embodiments, taxol) in Nanoparticulate compositions include But it is not limited to, about 50mg/m2、60mg/m2、75mg/m2、80mg/m2、90mg/m2、100mg/m2、120mg/m2、140mg/m2、 150mg/m2、160mg/m2、175mg/m2、200mg/m2、210mg/m2、220mg/m2、260mg/m2And 300mg/m2In any It is a.For example, dosage of the taxol in Nanoparticulate compositions can be within the scope of the following：About 100- when arranging to give based on 3 weeks 400mg/m2, or based on about 50-250mg/m when arranging to give weekly2。
In some embodiments, the method that individual (for example, people) melanoma for the treatment of is provided, including give individual effective dose Include contain taxane (for example, taxol) and carrier protein (for example, albumin, such as human serum albumins or human albumin) Nano particle composition, wherein dosage of the taxane in Nanoparticulate compositions is in about 50mg/m2To about 400mg/m2It Between (including for example, about 100mg/m2To about 300mg/m2, about 100mg/m2To about 200mg/m2Or about 125mg/m2To about 175mg/m2).In some embodiments, the taxane amount (dosage) in Nanoparticulate compositions is in about 100mg/m2To about 300mg/m2Between (for example, about 100mg/m2To about 200mg/m2).In some embodiments, in Nanoparticulate compositions Taxane amount (dosage) is in about 125mg/m2To about 175mg/m2Between (for example, about 100mg/m2Or about 150mg/m2).At some In embodiment, Nanoparticulate compositions being given weekly for three weeks in surrounding, or given weekly.In some embodiments In, carrier protein is albumin, such as human serum albumins or human albumin.In some embodiments, taxane is taxol.
In some embodiments, the method that individual (for example, people) melanoma for the treatment of is provided, including give individual effective dose Include contain taxane (for example, taxol) and carrier protein (for example, albumin, such as human serum albumins or human albumin) Nano particle composition, wherein dosage of the taxane in Nanoparticulate compositions is in about 50mg/m2To about 400mg/m2It Between (including for example, about 100mg/m2To about 300mg/m2, about 100mg/m2To about 200mg/m2Or about 125mg/m2To about 175mg/m2).In some embodiments, the taxane amount (dosage) in Nanoparticulate compositions is in about 100mg/m2To about 300mg/m2Between (for example, about 100mg/m2To about 200mg/m2, such as from about 100mg/m2Or about 150mg/m2).In some embodiment party In formula, the taxane amount (dosage) in Nanoparticulate compositions is in about 100mg/m2To about 200mg/m2Between (for example, about 100mg/m2Or about 150mg/m2).In some embodiments, Nanoparticulate compositions being given weekly for three weeks in surrounding, Or it is given weekly.In some embodiments, individual has IV stages or metastatic melanoma (for example, IV stages or transfer Property cutaneous melanoma).In some embodiments, melanoma is metastatic malignant melanoma.In some embodiments, it shifts Property melanoma is in M1a stages, M1b stages or M1c stages.In some embodiments, metastatic melanoma is in the M1c stages. In some embodiments, melanoma includes the mutation of BRAF.In some embodiments, melanoma does not include the mutation of BRAF. In some embodiments, melanoma include BRAF mutant, such as activity increase (for example, kinase activity increase and/or with open country Raw type BRAF increases compared to activity) BRAF mutant or the enhanced mutant of BRAF functions.In some embodiments, melanocyte Tumor does not include BRAF V600E mutation (for example, melanoma includes wild type BRAF).In some embodiments, melanoma includes Wild type BRAF.In some embodiments, melanoma includes BRAF mutant, and such as activity increases (for example, kinase activity increases And/or compared with wild type BRAF activity increase) BRAF mutant or the enhanced mutant of BRAF functions.In some embodiment party In formula, melanoma includes BRAF V600E mutation.In some embodiments, individual has raised Serum LDH horizontal.One In a little embodiments, individual has about following any Serum LDH：<0.8×ULN、0.4-0.8×ULN、0.8-1.1× ULN, 0.9-1.1 × ULN, 0.8-1.2 × ULN, 1.1-1.5 × ULN, 1.2-1.5 × ULN, 1.1-2 × ULN or 1.5-2 × ULN.In some embodiments, individual has the Serum LDH less than about 0.8 × ULN.In some embodiments, individual tool Have about 0.8 × to the Serum LDH of about 1.1 × ULN.In some embodiments, individual have greater than about 1.1 × to about 2.0 × Serum LDH between ULN.In some embodiments, individual have about 1.1 × to the Serum LDH between about 2.0 × ULN. In some embodiments, individual is people's (for example, sex).In some embodiments, taxane is taxol.One In a little embodiments, carrier protein is albumin.
Nanoparticulate compositions can be given individual (such as people) in several ways, including, for example, parenteral, the intravenous, heart Interior, intra-arterial, in peritonaeum, intrapulmonary, oral, sucking, intracapsular, intramuscular, tracheal strips, subcutaneously, intraocular, intrathecal, transmucosal and warp Skin.In some embodiments, the sustained continuous release formulations of composition can be used.In some embodiments, composition quilt Intravenous administration.In some embodiments, composition is given by portal vein.In some embodiments, composition is by artery Inside give.In some embodiments, composition is given in peritonaeum.In some embodiments, composition is given by intrathecal. In some embodiments, composition is given by ported catheter (ported catheter) to spinal fluid.In some implementations In mode, composition is given by intra-ventricle.In some embodiments, composition is given by systemic.In some embodiments In, composition is given by perfusion.In some embodiments, composition via implantable pump perfusion by being given.At some In embodiment, composition is given by ventricular catheter.In some embodiments, composition passes through port or port tube (portacath) it gives.In some embodiments, port or port tube be inserted into vein (such as jugular vein, subclavian vein or Superior vena cava).
Therapeutic regimen as described herein is suitable for monotherapy and combination treatment is set.The administration route of combination therapy It is described further below.
The administration route of combination treatment
Provided herein is in the way of combination therapy to treat melanoma and administration.In some embodiments, treatment is provided The method of individual (for example, people) melanoma, including give it is individual a) a effective amount of include containing taxane (for example, taxol) and The composition and b of the nano particle of carrier protein (for example, albumin)) a effective amount of at least one other agent (such as chemotherapeutics or Immunotherapeutic agent).It includes containing taxane (for example, taxol) and carrier protein (for example, albumin) to be described herein utilization It the composition of nano particle and the mode of other agent and gives.
Including the composition (also referred to as " Nanoparticulate compositions ") of the nano particle containing taxane and other agent can Simultaneously (that is, giving simultaneously) and/or successively (that is, giving in succession) is given.
In some embodiments, Nanoparticulate compositions and other agent (including specific agent as described herein) are given simultaneously It gives.Term " is given " simultaneously, as used herein, means that the time interval that Nanoparticulate compositions and other agent are given is not more than About 15 minutes (one or more) is such as not greater than about any of 10,5 or 1 minutes.When drug is given simultaneously, nanometer Drug and other agent in particle can be comprised in identical composition (for example, composition includes nano particle and other agent) Or individually in composition (for example, nano particle is comprised in a kind of composition, and other agent are comprised in another composition In).
In some embodiments, Nanoparticulate compositions and other agent are given in succession.Term " is given " in succession, such as originally Used in text, mean that time interval that drug in Nanoparticulate compositions and other agent are given is greater than about 15 minutes, such as larger than About 20,30,40,50, any of 60 or more minutes.Any one in Nanoparticulate compositions or other agent can first by It gives.Nanoparticulate compositions and other agent are comprised in individual composition, and the composition can be comprised in identical or different Packaging in.
In some embodiments, Nanoparticulate compositions are synchronous with giving for other agent, that is, nano particle combines The period of giving for giving period and other agent of object overlaps each other.In some embodiments, Nanoparticulate compositions are being given At least one period (for example, any of at least 2,3 or 4 periods) is given before other agent.In some embodiments, Other agent are given any one of at least 1,2,3 or 4 week.In some embodiments, Nanoparticulate compositions and other agent Give at about (for example, within any of 1,2,3,4,5,6 or 7 day) beginning.In some embodiments, nanometer Grain composition and giving for other agent at about (for example, within any of 1,2,3,4,5,6 or 7 day) are terminated.At some In embodiment, giving for other agent continue after giving in Nanoparticulate compositions (for example, about 1,2,3,4,5,6,7, 8,9,10,11 or any of 12 months).In some embodiments, other agent give Nanoparticulate compositions to It gives and starting (for example, after any of about 1,2,3,4,5,6,7,8,9,10,11 or 12 months) after starting.In some implementations In mode, Nanoparticulate compositions give at about starting and ending with other agent.In some embodiments, nanometer Grain composition and giving for other agent at about start, and giving for other agent is terminated in giving for Nanoparticulate compositions Continue (for example, either one or two of about 1,2,3,4,5,6,7,8,9,10,11 or 12 middle of the month) afterwards.In some embodiments, it receives Rice grain composition and giving for other agent at about stop, and giving in Nanoparticulate compositions is given in other agent (for example, after about 1,2,3,4,5,6,7,8,9,10,11 or any of 12 months) start after beginning.
In some embodiments, Nanoparticulate compositions are synchronous with giving for other agent (for example, carboplatin), that is, The period of giving for giving period and other agent of Nanoparticulate compositions overlaps each other.In some embodiments, nano particle Composition and giving for other agent at about (for example, within any of 1,2,3,4,5,6 or 7 day) start.At some In embodiment, Nanoparticulate compositions are given at about with other agent (for example, any in 1,2,3,4,5,6 or 7 day Within a) terminate.In some embodiments, giving for other agent terminates to continue later in giving for Nanoparticulate compositions (for example, either one or two of about 1,2,3,4,5,6,7,8,9,10,11 or 12 middle of the month).In some embodiments, other agent It gives after the giving of Nanoparticulate compositions (for example, any about 1,2,3,4,5,6,7,8,9,10,11 or 12 middle of the month After a) start.In some embodiments, at about beginning and end is given in Nanoparticulate compositions and other agent. In some embodiments, Nanoparticulate compositions and giving for other agent at about start, and other agent are given Giving for Nanoparticulate compositions terminates to continue later (for example, times in about 1,2,3,4,5,6,7,8,9,10,11 or 12 middle of the month One).In some embodiments, Nanoparticulate compositions and giving for other agent at about stop, and other agent It gives after the giving of Nanoparticulate compositions (for example, any about 1,2,3,4,5,6,7,8,9,10,11 or 12 middle of the month After a) start.In some embodiments, method includes being more than a treatment cycle, and at least one wherein in treatment cycle A includes that it is a effective amount of to give (a) includes the nanometer containing taxane (such as taxol) and carrier protein (for example, albumin) The composition of grain；(b) other a effective amount of at least one agent.In some embodiments, treatment cycle includes not less than about (such as from about) 21 days (for example, 4 weeks).In some embodiments, treatment cycle includes being less than about 21 days (for example, weekly or often It).In some embodiments, treatment cycle includes about 28 days.
In some embodiments, Nanoparticulate compositions and giving for other agent are asynchronous.For example, in some realities It applies in mode, giving for Nanoparticulate compositions terminates before giving other agent.In some embodiments, other agent are given It gives and terminating before giving Nanoparticulate compositions.The two are asynchronous give between period can be in about 2 to 8 all ranges It is interior, such as from about 4 weeks.
Including the Nanoparticulate compositions of drug and the medicine frequency of other agent can treated based on the judgement of administration doctor Period is adjusted.When individually being given, including the medicine frequency that the Nanoparticulate compositions of drug and other agent can be different Or interval is given.For example, the Nanoparticulate compositions comprising drug can be given weekly, and other agent can be higher or lower Frequency is given.In some embodiments, the nano particle comprising drug and/or the release of the sustained continuous of other agent can be used Preparation.The various preparations and device for realizing sustained release are known in the art.Exemplary medicine frequency further provided herein.
Nanoparticulate compositions and other agent can be given with identical administration route or different administration routes.Herein into one Step provides exemplary administration route.In some embodiments (for giving simultaneously and in succession), in Nanoparticulate compositions Taxane and other agent are given with predetermined ratio.For example, in some embodiments, taxane in Nanoparticulate compositions and its The weight ratio of his agent is about 1 to 1.In some embodiments, the weight ratio can about 0.001 to about 1 and about 1000 to about 1 it Between or about 0.01 to about 1 and 100 to about 1 between.In some embodiments, the taxane in Nanoparticulate compositions and other The weight ratio of agent is less than about 100：1、50：1、30：1、10：1、9：1、8：1、7：1、6：1、5：1、4：1、3：1、2：1 and 1：In 1 Any one.In some embodiments, the taxane in Nanoparticulate compositions and the weight ratio of other agent are greater than about 1：1、2： 1、3：1、4：1、5：1、6：1、7：1、8：1、9：1、30：1、50：1、100：Any of 1.Consider other ratios.
Taxane and/or the required dosage of other agent can (but not necessarily) be less than the normal need when individually giving each dose Dosage.Therefore, in some embodiments, the drug in the Nanoparticulate compositions of asian treatment amount and/or other agent are given. " asian treatment amount " or " asian treatment horizontal " refers to the amount less than therapeutic dose, that is, less than individually giving in Nanoparticulate compositions Normal usage when drug and/or other agent.This reduction can be reflected in given administration administered dose and/or given period to In terms of the amount of giving (frequency reduction).
In some embodiments, other enough agent are given, so as to generate the nanometer needed for the treatment of same degree Grain composition drug normal dose be reduced by least about 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90% or It is any of more.In some embodiments, drug enough in Nanoparticulate compositions is given, so as to generate identical journey The normal dose of other agent needed for the treatment of degree is reduced by least about 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, any of 90% or more.
In some embodiments, it is each when the taxane in Nanoparticulate compositions and the dosage of other agent are with independent give It compares from corresponding normal dose and is all reduced.In some embodiments, with asian treatment level, that is, the level reduced is given Give the taxane in Nanoparticulate compositions and other agent.In some embodiments, the dosage of Nanoparticulate compositions and/or Other agent are significantly less than the maximum toxicity dose (MTD) established.For example, Nanoparticulate compositions and/or the dosage of other agent About 50%, 40%, 30%, 20% or 10% less than MTD.
In some embodiments, the dosage of taxane and/or the dosage of other agent are normal at each dose higher than individually giving The dosage needed.For example, in some embodiments, the dosage of Nanoparticulate compositions and/or other agent is significantly higher than really Vertical maximum toxicity dose (MTD).For example, when Nanoparticulate compositions and/or the dosage of other agent are more than individually medicament is given MTD about 50%, 40%, 30%, 20% or 10%.
In some embodiments, the taxane (for example, taxol) that composition includes is measured within the scope of opinion row in office： About 0.5 to about 5mg, about 5 to about 10mg, about 10 to about 15mg, about 15 to about 20mg, about 20 to about 25mg, about 20 to about 50mg, About 25 to about 50mg, about 50 to about 75mg, about 50 to about 100mg, about 75 to about 100mg, about 100 to about 125mg, about 125 to About 150mg, about 150 to about 175mg, about 175 to about 200mg, about 200 to about 225mg, about 225 to about 250mg, about 250 are to about 300mg, about 300 to about 350mg, about 350 to about 400mg, about 400 to about 450mg or about 450 to about 500mg.In some implementations In mode, taxane (for example, taxol) in a effective amount of composition (for example, unit dosage forms) or derivatives thereof measures (dosage) Within the scope of the following：About 5mg to about 500mg, such as from about 30mg are to about 300mg or about 50mg to about 200mg.In some embodiments In, the concentration of taxane (for example, taxol) in the composition is dilute (about 0.1mg/ml) or dense (about 100mg/ml), packet Include, for example, about 0.1 to about 50mg/ml, about 0.1 to about 20mg/ml, about 1 to about 10mg/ml, about 2mg/ml to about 8mg/ml, About 4 to about 6mg/ml, about any of 5mg/ml.In some embodiments, taxane (for example, taxol) is a concentration of At least about 0.5mg/ml, 1.3mg/ml, 1.5mg/ml, 2mg/ml, 3mg/ml, 4mg/ml, 5mg/ml, 6mg/ml, 7mg/ml, Appointing in 8mg/ml, 9mg/ml, 10mg/ml, 15mg/ml, 20mg/ml, 25mg/ml, 30mg/ml, 40mg/ml or 50mg/ml One.
Exemplary taxane (for example, taxol) in Nanoparticulate compositions measures (dosage), at least About 25mg/m2、30mg/m2、50mg/m2、60mg/m2、75mg/m2、80mg/m2、90mg/m2、100mg/m2、120mg/m2、 125mg/m2、150mg/m2、160mg/m2、175mg/m2、180mg/m2、200mg/m2、210mg/m2、220mg/m2、250mg/ m2、260mg/m2、300mg/m2、350mg/m2、400mg/m2、500mg/m2、540mg/m2、750mg/m2、1000mg/m2Or 1080mg/m2Any of taxane (for example, taxol).In different embodiments, composition includes being less than about 350mg/m2、300mg/m2、250mg/m2、200mg/m2、150mg/m2、120mg/m2、100mg/m2、90mg/m2、50mg/m2Or 30mg/m2Any of taxane (for example, taxol).In some embodiments, give every time taxane (for example, Taxol) it measures less than about 25mg/m2、22mg/m2、20mg/m2、18mg/m2、15mg/m2、14mg/m2、13mg/m2、12mg/m2、 11mg/m2、10mg/m2、9mg/m2、8mg/m2、7mg/m2、6mg/m2、5mg/m2、4mg/m2、3mg/m2、2mg/m2Or 1mg/m2In Either one or two of.In some embodiments, taxane (for example, taxol) amount (dosage) the opinion row in office that composition includes In range：About 1 to about 5mg/m2, about 5 to about 10mg/m2, about 10 to about 25mg/m2, about 25 to about 50mg/m2, about 50 to about 75mg/m2, about 75 to about 100mg/m2, about 100 to about 125mg/m2, about 125 to about 150mg/m2, about 150 to about 175mg/m2、 About 175 to about 200mg/m2, about 200 to about 225mg/m2, about 225 to about 250mg/m2, about 250 to about 300mg/m2, about 300 To about 350mg/m2Or about 350 to about 400mg/m2.In some embodiments, the taxane in composition (for example, taxol) It is about 5 to about 300mg/m to measure (dosage)2, such as from about 20 to about 300mg/m2, about 50 to about 250mg/m2, about 100 to about 150mg/ m2, about 120mg/m2, about 130mg/m2Or about 140mg/m2Or about 260mg/m2。
In some embodiments of any of the above-described aspect, taxane (for example, taxol) amount (dosage) in composition Including at least about 1mg/kg, 2.5mg/kg, 3.5mg/kg, 5mg/kg, 6.5mg/kg, 7.5mg/kg, 10mg/kg, 15mg/kg or Any of 20mg/kg.In different embodiments, the taxane in composition (for example, taxol) amount (dosage) includes Less than about 350mg/kg, 300mg/kg, 250mg/kg, 200mg/kg, 150mg/kg, 100mg/kg, 50mg/kg, 25mg/kg, Any of 20mg/kg, 10mg/kg, 7.5mg/kg, 6.5mg/kg, 5mg/kg, 3.5mg/kg, 2.5mg/kg or 1mg/kg's Taxane (for example, taxol).
The exemplary medicine frequency of Nanoparticulate compositions (and as described below, other agent) includes but not limited to, often It is all uninterrupted；Weekly, three weeks in surrounding；Once every three weeks；Once every two weeks；Weekly, two weeks in three weeks.In some implementations In mode, give composition about once every 2 weeks, every 3 weeks primary, every 6 weeks primary, every 4 weeks it is primary or every 8 weeks primary.At some In embodiment, give composition at least about one week 1 ×, 2 ×, 3 ×, 4 ×, 5 ×, any in 6 × or 7 × (that is, daily) It is a or three times a day, twice daily.In some embodiments, interval between giving every time be less than about 6 months, 3 months, 1 Any of a month, 20 days, 15 days, 12 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day.One In a little embodiments, the interval between giving every time is greater than about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 Either one or two of the moon or 12 middle of the month.In some embodiments, free of discontinuities in medication schedule.In some embodiments, every time Interval between giving is not greater than about one week.
In some embodiments, the taxane in Nanoparticulate compositions is given weekly.In some embodiments, Taxane in Nanoparticulate compositions is given every two weeks.In some embodiments, the Japanese yew in Nanoparticulate compositions Alkane is given for every three weeks.In some embodiments, other agent be given one week 1 ×, 2 ×, 3 ×, 4 ×, 5 ×, 6 × or 7 times. In some embodiments, two weeks in other agent every two weeks or three weeks are given.In some embodiments, taxane is purple China fir alcohol.In some embodiments, other agent are platinum base agent (such as carboplatins).In above-mentioned dosage and/or some embodiment party of administration In formula, taxane is taxol, and other agent are carboplatins.
Nanoparticulate compositions (and other agent) are given and can be continued for a long time, and such as from about one month up to about seven years.One In a little embodiments, composition is given at least about 2,3,4,5,6,7,8,9,10,11,12,18,24,30,36,48,60,72 Or any of 84 months time.In some embodiments, taxane (for example, taxol) is given at least one month Time, wherein the interval between giving every time is not greater than about one week, and the taxane (for example, taxol) wherein given every time Dosage is about 0.25mg/m2To about 75mg/m2, such as from about 0.25mg/m2To about 25mg/m2Or about 25mg/m2To about 50mg/m2。
The medicine frequency of other agent (for example, platinum base agent, such as carboplatin) can be identical or different with Nanoparticulate compositions.Above Provide example frequency.As further example, can give other agent three times a day, twice a day, once a day (daily), One Saturday time, five times one week, a Thursday time, three times a week, biweekly, weekly week two Mondays (weekly), in three weeks Three weeks in primary or surrounding are weekly.In some embodiments, other agent are given twice a day or three times a day.
In some embodiments, dosage of the taxane (for example, taxol) in Nanoparticulate compositions can be following In range：5-400mg/m was arranged based on 3 weeks2Or based on arranging 5-250mg/m weekly2.For example, taxane (for example, taxol) Amount was arranging the when given to can be about 60 to about 300mg/m based on three weeks2(for example, about 260mg/m2)。
Give other exemplary medications of Nanoparticulate compositions (for example, taxol/albumin nanoparticle composition) Arrangement includes but not limited to 100mg/m2, weekly, free of discontinuities；75mg/m2, weekly, three weeks in surrounding；100mg/m2, weekly, Three weeks in surrounding；125mg/m2, weekly, three weeks in surrounding；125mg/m2, weekly, 2 weeks in 3 weeks；130mg/m2, often It is week, free of discontinuities；175mg/m2, once every 2 weeks；260mg/m2, once every 2 weeks；260mg/m2, every 3 weeks once；180-300mg/ m2, every three weeks；60-175mg/m2, weekly, free of discontinuities；20-150mg/m2, biweekly；And 150-250mg/m2, one week two It is secondary.The medicine frequency of composition can be adjusted during treatment based on the judgement that doctor is administered.
In some embodiments, appointing in individual at least about 1,2,3,4,5,6,7,8,9 or 10 treatment cycle is treated One.Composition as described herein allows that composition is perfused to individual through shorter than about 24 hours infusion times.For example, at some In embodiment, composition pass through less than about 24 hours, 12 hours, 8 hours, 5 hours, 3 hours, 2 hours, 1 hour, 30 minutes, Any of 20 minutes or 10 minutes infusion times are given.In some embodiments, composition was perfused through about 30 minutes Time is given.
Other exemplary doses of taxane (in some embodiments, taxol) in Nanoparticulate compositions include But it is not limited to, about 50mg/m2、60mg/m2、75mg/m2、80mg/m2、90mg/m2、100mg/m2、120mg/m2、160mg/m2、 175mg/m2、200mg/m2、210mg/m2、220mg/m2、260mg/m2And 300mg/m2Any of.For example, taxol is being received Dosage in rice grain composition can be within the scope of the following：About 100-400mg/m when arranging to give based on 3 weeks2Or based on weekly About 50-250mg/m when arrangement is given2。
The dosage of other agent (for example, platinum base agent, such as carboplatin) can utilize methods known in the art to determine.For example, other The dosage of agent is contemplated that the creatinine clearance rate of individual, and blood plasma concentration curve area under is calculated by methods known in the art (AUC) it determines.The dosage of other agent can be adjusted (for example, reduction) based on the symptom (such as adverse reaction) of individual.At some In embodiment, it is computed with the dosage of other agent of taxane nano particle combined therapy and following AUC is provided：About 0.1- 10mg/ml min, about 1-8mg/ml min, about 1.5 to about 7.5mg/ml min, about 2 to about 6mg/ml min or about 1,2,3, 4, any of 5,6 or 7mg/ml min.Other agent, such as carboplatin can be given by whole body.Other agent can be by intravenous administration. Other agent can through about 10 to about 300 minutes, about 30 to about 180 minutes, about 45 to about 120 minutes or about 60 minutes time by It gives.
Other exemplary-amounts of other agent (for example, platinum base agent, such as carboplatin) include but not limited to following any range： About 0.5 to about 5mg, about 5 to about 10mg, about 10 to about 15mg, about 15 to about 20mg, about 20 to about 25mg, about 20 to about 50mg, About 25 to about 50mg, about 50 to about 75mg, about 50 to about 100mg, about 75 to about 100mg, about 100 to about 125mg, about 125 to About 150mg, about 150 to about 175mg, about 175 to about 200mg, about 200 to about 225mg, about 225 to about 250mg, about 250 are to about 300mg, about 300 to about 350mg, about 350 to about 400mg, about 400 to about 450mg or about 450 to about 500mg.For example, can give Give other agent of following dosage：About 1mg/kg to about 200mg/kg (including for example, about 1mg/kg to about 20mg/kg, about 20mg/ Kg to about 40mg/kg, about 40mg/kg are to about 60mg/kg, about 60mg/kg to about 80mg/kg, about 80mg/kg to about 100mg/ Kg, about 100mg/kg are to about 120mg/kg, about 120mg/kg to about 140mg/kg, about 140mg/kg to about 200mg/kg).
The dosage of other agent (for example, carboplatin) is contemplated that the creatinine clearance rate of individual, passes through methods known in the art meter Blood plasma concentration curve area under (AUC) is calculated to determine.The dosage of other agent can based on individual symptom (such as adverse reaction) into Row adjustment (for example, reduction).In some embodiments, other agent (such as the carboplatin with taxane nano particle combined therapy) Dosage, which is computed, provides following AUC：About 0.1-10mg/ml min, about 1-8mg/ml min, about 1.5 to about 7.5mg/ml min, Any of about 2 to about 6mg/ml min or about 1,2,3,4,5,6 or 7mg/ml min.Other agent, such as carboplatin, can be by whole body It gives.Other agent, such as carboplatin, can be by intravenous administration.Other agent, such as carboplatin can be given via port tube.Other agent, such as Carboplatin can through about 10 to about 300 minutes, about 30 to about 180 minutes, about 45 to about 120 minutes or about 60 minutes time by It gives.
The medicine frequency of other agent can be identical or different with Nanoparticulate compositions.Example frequency is provided above.Make For further example, other agent can be given three times a day, twice a day, (daily), a Saturday time, a Friday once a day Secondary, Thursday time, three times a week, biweekly, weekly (weekly).In some embodiments, other agent are given one It is twice or three times a day.
In some embodiments, the taxane amount (dosage) in Nanoparticulate compositions is in about 45mg/m2To about 350mg/m2Between, and the amount (dosage) of other agent be about 1mg/kg to about 200mg/kg (including for example, about 1mg/kg to about 20mg/kg, about 20mg/kg to about 40mg/kg, about 40mg/kg to about 60mg/kg, about 60mg/kg to about 80mg/kg, about 80mg/kg to about 100mg/kg, about 100mg/kg are to about 120mg/kg, about 120mg/kg to about 140mg/kg, about 140mg/kg To about 200mg/kg).In some embodiments, the taxane amount (dosage) in Nanoparticulate compositions is in about 80mg/m2Extremely About 350mg/m2Between, and the amount (dosage) of other agent be about 1mg/kg to about 200mg/kg (including for example, about 1mg/kg extremely About 20mg/kg, about 20mg/kg to about 40mg/kg, about 40mg/kg to about 60mg/kg, about 60mg/kg to about 80mg/kg, about 80mg/kg to about 100mg/kg, about 100mg/kg are to about 120mg/kg, about 120mg/kg to about 140mg/kg, about 140mg/kg To about 200mg/kg).In some embodiments, the taxane amount (dosage) in Nanoparticulate compositions is in about 80mg/m2Extremely About 300mg/m2Between, and the amount (dosage) of other agent be about 1mg/kg to about 200mg/kg (including for example, about 1mg/kg extremely About 20mg/kg, about 20mg/kg to about 40mg/kg, about 40mg/kg to about 60mg/kg, about 60mg/kg to about 80mg/kg, about 80mg/kg to about 100mg/kg, about 100mg/kg are to about 120mg/kg, about 120mg/kg to about 140mg/kg, about 140mg/kg To about 200mg/kg).In some embodiments, the taxane amount (dosage) in Nanoparticulate compositions is in about 150mg/m2Extremely About 350mg/m2Between, and the amount (dosage) of other agent be about 1mg/kg to about 200mg/kg (including for example, about 1mg/kg extremely About 20mg/kg, about 20mg/kg to about 40mg/kg, about 40mg/kg to about 60mg/kg, about 60mg/kg to about 80mg/kg, about 80mg/kg to about 100mg/kg, about 100mg/kg are to about 120mg/kg, about 120mg/kg to about 140mg/kg, about 140mg/kg To about 200mg/kg).In some embodiments, the taxane amount (dosage) in Nanoparticulate compositions is in about 80mg/m2Extremely About 150mg/m2Between, and the amount (dosage) of other agent be about 1mg/kg to about 200mg/kg (including for example, about 1mg/kg extremely About 20mg/kg, about 20mg/kg to about 40mg/kg, about 40mg/kg to about 60mg/kg, about 60mg/kg to about 80mg/kg, about 80mg/kg to about 100mg/kg, about 100mg/kg are to about 120mg/kg, about 120mg/kg to about 140mg/kg, about 140mg/kg To about 200mg/kg).In some embodiments, the taxane in Nanoparticulate compositions (for example, taxol) amount (dosage) It is about 100mg/m2.In some embodiments, the taxane amount (dosage) in Nanoparticulate compositions is in about 170mg/m2To about 200mg/m2Between, and the amount (dosage) of other agent be about 1mg/kg to about 200mg/kg (including for example, about 1mg/kg to about 20mg/kg, about 20mg/kg to about 40mg/kg, about 40mg/kg to about 60mg/kg, about 60mg/kg to about 80mg/kg, about 80mg/kg to about 100mg/kg, about 100mg/kg are to about 120mg/kg, about 120mg/kg to about 140mg/kg, about 140mg/kg To about 200mg/kg).In some embodiments, the taxane amount (dosage) in Nanoparticulate compositions is in about 200mg/m2Extremely About 350mg/m2Between, and the amount (dosage) of other agent be about 1mg/kg to about 200mg/kg (including for example, about 1mg/kg extremely About 20mg/kg, about 20mg/kg to about 40mg/kg, about 40mg/kg to about 60mg/kg, about 60mg/kg to about 80mg/kg, about 80mg/kg to about 100mg/kg, about 100mg/kg are to about 120mg/kg, about 120mg/kg to about 140mg/kg, about 140mg/kg To about 200mg/kg).In some embodiments, the taxane in Nanoparticulate compositions (for example, taxol) amount (dosage) It is about 260mg/m2.In some embodiments of above-mentioned any means, the amounts (dosage) of other agent is about 20-30mg/kg, about 30-40mg/kg, about 40-50mg/kg, about 50-60mg/kg, about 60-70mg/kg, about 70-80mg/kg, about 80-100mg/kg Or about 100-120mg/kg.
In some embodiments, the taxane amount (dosage) in Nanoparticulate compositions is in about 45mg/m2To about 350mg/m2Between, and the amount (dosage) of other agent be about 80mg to about 1000mg (including for example, about 80 to about 100mg, about 100 to about 200mg, about 200 to about 300mg, about 300 to about 400mg, about 400 to about 500mg, about 500 to about 600mg, about 600 to about 700mg, about 700 to about 800mg, about 800 to about 900mg, about 900mg to about 1000mg).In some embodiments In, the taxane amount (dosage) in Nanoparticulate compositions is in about 80mg/m2To about 350mg/m2Between, and the amount (agent of other agent Amount) be about 80mg to about 1000mg (including for example, about 80 to about 100mg, about 100 to about 200mg, about 200 to about 300mg, About 300 to about 400mg, about 400 to about 500mg, about 500 to about 600mg, about 600 to about 700mg, about 700 to about 800mg, about 800 to about 900mg, about 900mg to about 1000mg).In some embodiments, the taxane amount in Nanoparticulate compositions (dosage) is in about 80mg/m2To about 300mg/m2Between, and the amount (dosage) of other agent is about 80mg to about 1000mg (including examples Such as, about 80 to about 100mg, about 100 to about 200mg, about 200 to about 300mg, about 300 to about 400mg, about 400 to about 500mg, About 500 to about 600mg, about 600 to about 700mg, about 700 to about 800mg, about 800 to about 900mg, about 900mg is to about 1000mg).In some embodiments, the taxane amount (dosage) in Nanoparticulate compositions is in about 150mg/m2To about 350mg/m2Between, and the amount (dosage) of other agent be about 80mg to about 1000mg (including for example, about 80 to about 100mg, about 100 to about 200mg, about 200 to about 300mg, about 300 to about 400mg, about 400 to about 500mg, about 500 to about 600mg, about 600 to about 700mg, about 700 to about 800mg, about 800 to about 900mg, about 900mg to about 1000mg).In some embodiments In, the taxane amount (dosage) in Nanoparticulate compositions is in about 80mg/m2To about 150mg/m2Between, and the amount (agent of other agent Amount) be about 80mg to about 1000mg (including for example, about 80 to about 100mg, about 100 to about 200mg, about 200 to about 300mg, About 300 to about 400mg, about 400 to about 500mg, about 500 to about 600mg, about 600 to about 700mg, about 700 to about 800mg, about 800 to about 900mg, about 900mg to about 1000mg).In some embodiments, the taxane amount in Nanoparticulate compositions (dosage) is in about 170mg/m2To about 200mg/m2Between, and the amount (dosage) of other agent be about 80mg to about 1000mg (including For example, about 80 to about 100mg, about 100 to about 200mg, about 200 to about 300mg, about 300 to about 400mg, about 400 to about 500mg, about 500 to about 600mg, about 600 to about 700mg, about 700 to about 800mg, about 800 to about 900mg, about 900mg are to about 1000mg).In some embodiments, the taxane amount (dosage) in Nanoparticulate compositions is in about 200mg/m2To about 350mg/m2Between, and the amount (dosage) of other agent be about 80mg to about 1000mg (including for example, about 80 to about 100mg, about 100 to about 200mg, about 200 to about 300mg, about 300 to about 400mg, about 400 to about 500mg, about 500 to about 600mg, about 600 to about 700mg, about 700 to about 800mg, about 800 to about 900mg, about 900mg to about 1000mg).In some embodiments In, taxane (for example, taxol) amount (dosage) in Nanoparticulate compositions is about 100mg/m2.In above-mentioned any means In some embodiments, the amounts (dosage) of other agent is about 100-200mg, about 200-300mg, about 300-400mg, about 400- 500mg。
In some embodiments, the taxane amount (dosage) in Nanoparticulate compositions is in about 50mg/m2To about 400mg/m2Between (including for example, about 100mg/m2To about 300mg/m2, about 75mg/m2To about 150mg/m2Or about 100mg/m2 To about 150mg/m2), and the amount (dosage) of other agent (for example, carboplatin) is about AUC1 to about AUC7 (including for example, about AUC2 To about AUC6 or about any of AUC1, AUC2, AUC3, AUC4, AUC5 or AUC6).In some embodiments, nanometer Taxane amount (dosage) in grain composition is in about 100mg/m2To about 300mg/m2Between (for example, about 100mg/m2To about 150mg/m2), and the amount (dosage) of other agent is about AUC2 to about AUC6 (for example, about AUC2, AUC3, AUC4, AUC5 or AUC6 Any of).In some embodiments, the taxane amount (dosage) in Nanoparticulate compositions is in about 100mg/m2To about 150mg/m2Between, and the amount (dosage) of other agent be about AUC4 to about AUC6 (for example, about in AUC4, AUC5 or AUC6 appoint One).
In some embodiments, the method for treating individual (for example, people) melanoma is provided, including give individual (a) to have Effect amount includes containing taxane (for example, taxol) and carrier protein (for example, albumin, as human serum albumins or people are white Albumen) nano particle composition and (b) other a effective amount of at least one agent (for example, carboplatin), wherein taxane receiving Dosage in rice grain composition is in about 50mg/m2To about 400mg/m2Between (including for example, about 100mg/m2To about 300mg/ m2, about 100mg/m2To about 200mg/m2Or about 100mg/m2To about 150mg/m2Or about 100mg/m2Or about 150mg/m2), and its The dosage of his agent (for example, carboplatin) be about AUC1 to about AUC7 (including for example, about AUC2 to about AUC6 or about AUC1, AUC2, Any of AUC3, AUC4, AUC5 or AUC6).In some embodiments, three weeks in surrounding of Nanoparticulate compositions It is given weekly, or is given weekly.In some embodiments, other agent being given weekly for three weeks in surrounding, or by It gives weekly.In some embodiments, carrier protein is albumin, such as human serum albumins or human albumin.In some realities It applies in mode, taxane is taxol.In some embodiments, other agent are platinum base agent.In some embodiments, other Agent is carboplatin.
Nanoparticulate compositions (and other agent) as described herein can be given individual (such as people) via number of ways, including, For example, in intravenous, intra-arterial, peritonaeum, intrapulmonary, oral, sucking, intracapsular, intramuscular, tracheal strips, subcutaneous, intraocular, it is intrathecal, through gluing Film and percutaneous.In some embodiments, the sustained continuous release formulations of composition can be used.In a kind of modification of the present invention In, nano particle (such as albumin nanoparticle) can be given by any acceptable approach：Including but not limited to, take orally, Delivery system and similar approach intramuscular, percutaneous, intravenous, by inhalator or the carrying of other air.It is any to can be used for giving The approach of Nanoparticulate compositions as described herein can be used for giving other agent.Other agent as described herein can be via number of ways Be given individual (such as people), as in parenteral including intravenous, intra-ventricle, intra-arterial, peritonaeum, intrapulmonary, oral, sucking, capsule It is interior, intramuscular, tracheal strips, subcutaneous, intraocular, intrathecal or percutaneous.In some embodiments, other agent are given by whole body.At some In embodiment, other agent are by intravenous administration.In some embodiments, other agent are given by perfusion.In some realities It applies in mode, other agent are given by port or port tube.In some embodiments, Nanoparticulate compositions taken orally to It gives.
It will be appreciated by those skilled in the art that the suitable dosage of other agent is about to have been used to the dosage of clinical treatment, wherein Other agent are given by agent other alone or in combination.Doses change will likely exist according to treatment situation.As described above, one In a little embodiments, other agent can be given under the level of reduction.
The combination of administration configuration described herein can be used.Combination therapy as described herein can be carried out individually or be combined another Outer therapy, such as chemotherapy, radiotherapy (for example, whole brain radiation therapy), operation, hormonotherapy, gene therapy, immune treatment Method, chemoimmunotherapy, cold therapy, ultrasonic therapy, liver transfer operation, local ablation therapy, radio frequency ablation therapy, photodynamic therapy And homoeopathy.The acceptable treatment of the larger people of proliferative disease risk occurs to inhibit and/or postpone the generation of disease.
Nanoparticulate compositions
Nanoparticulate compositions as described herein include nano particle, (in different embodiments, which includes It is mainly made of following)：Taxane (such as taxol) and carrier protein (for example, albumin, such as human serum albumins or the white egg of people In vain).The nano particle of weak water-soluble drug (such as taxane) has been disclosed, for example, U.S. Patent number 5,916,596；6, 506,405；6,749,868,6,537,579,7,820,788 and U.S. Patent Publication No. 2006/0263434 and 2007/ 0082838；PCT Patent Application WO08/137148, entire contents are incorporated by reference herein.
In some embodiments, composition includes nano particle, and the average or mean value diameter of the nano particle is not more than About 1000 nanometers (nm), as no more than about in (or being less than about) 900,800,700,600,500,400,300,200 and 100nm Any one.In some embodiments, the average or mean value diameter of nano particle is not greater than about 200nm (such as less than about 200nm). In some embodiments, the average or mean value diameter of nano particle is not greater than about 150nm.In some embodiments, nanometer The average or mean value diameter of particle is not greater than about 100nm.In some embodiments, the average or mean value of nano particle is a diameter of About 20 to about 400nm.In some embodiments, the average or mean value a diameter of about 40 to about 200nm of nano particle.At some In embodiment, nano particle can be sterile filtered.
In some embodiments, the nano particle of composition as described herein has following average diameter：It is not greater than about 200nm, including, for example, no more than about 190,180,170,160,150,140,130,120,110,100,90,80,70 or Any of 60nm.In some embodiments, at least about 50% in composition (for example, at least about 60%, 70%, 80%, 90%, any of 95% or 99%) nano particle has following diameter：No more than about 200nm, including, for example, less In any of about 190,180,170,160,150,140,130,120,110,100,90,80,70 or 60nm.In some realities It applies in mode, (for example, any at least 60%, 70%, 80%, 90%, 95% or 99% at least about 50% in composition It is a) nano particle fall into following range：About 20 to about 400nm, including, for example, about 20 to about 200nm, about 40 to about 200nm, about 30 are to about 180nm, and about 40 to about 150, about 50 to about 120 and about 60 to about any of 100nm.
In some embodiments, carrier protein (for example, albumin) has the sulfydryl that can form disulfide bond (sulfhydral).In some embodiments, at least about 5% in the nano particle portion of composition (including for example, at least Any of about 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80% or 90%) carrier egg (for example, albumin) crosslinking (for example, passing through one or more disulfide bond crosslinkings) in vain.
In some embodiments, nano particle be coated with carrier protein (for example, albumin, such as human albumin or Human serum albumins) taxane (such as taxol).In some embodiments, composition includes nano particle and non-nano The taxane (for example, paclitaxel solution form or soluble carrier albumen/nano-particle complex form) of particle shape formula, wherein group The taxane for closing in object at least about 50%, 60%, 70%, 80%, 90%, any of 95% or 99% is nano particle shape Formula.In some embodiments, the taxane in nano particle form more than about 50% by weight, 60%, 70%, 80%, 90%, any of 95% or 99% nano particle.In some embodiments, nano particle has nonpolymer matrix. In some embodiments, nano particle includes the taxane kernel of substantially non-polymer material (such as polymer substrate).
In some embodiments, composition includes the carrier protein in composition nano particle and non-nanoparticulate part (for example, albumin), any of at least about 50%, 60%, 70%, 80%, 90%, 95% or 99% wherein in composition Carrier protein (for example, albumin) is in composition non-nanoparticulate part.
In some embodiments, albumin (such as human albumin or human serum albumins) and purple in Nanoparticulate compositions The weight ratio of China fir alkane is about 18：1 or smaller, such as from about 15：1 or smaller, for example, about 10：1 or smaller.In some embodiments, Albumin (such as human albumin or human serum albumins) and the weight ratio of taxane are fallen into following any range in composition：About 1：1 to about 18：1, about 2：1 to about 15：1, about 3：1 to about 13：1, about 4：1 to about 12：1, about 5：1 to about 10：1.In some realities It applies in mode, the weight ratio of albumin and taxane is about 1 in composition nano particle portion：2、1：3、1：4、1：5、1：9,1： 10、1：Any of 15 or smaller.In some embodiments, albumin (such as human albumin or human seralbumin in composition Albumen) with the weight ratio of taxane be it is following any one：About 1：1 to about 18：1, about 1：1 to about 15：1, about 1：1 to about 12：1、 About 1：1 to about 10：1, about 1：1 to about 9：1, about 1：1 to about 8：1, about 1：1 to about 7：1, about 1：1 to about 6：1, about 1：1 to about 5： 1, about 1：1 to about 4：1, about 1：1 to about 3：1, about 1：1 to about 2：1, about 1：1 to about 1：1.
In some embodiments, Nanoparticulate compositions include one or more of features described above.
Nano particle as described herein may be present in drying agent (such as freeze-dried composition) or be suspended in biocompatibility In medium.Biocompatible media appropriate includes but not limited to, water, aqueous buffered medium, brine, buffered saline, optionally Buffered with amino acid solution, optionally protein buffer solution, optionally sugar buffer solution, optionally vitamin buffer solution are appointed Selection of land synthetic polymer buffer solution contains Lipid emulsions and analog.
In some embodiments, pharmaceutically acceptable carrier includes carrier protein (for example, albumin, such as the white egg of people White or human serum albumins).The example of carrier protein appropriate includes the protein being typically found in blood or blood plasma, including But it is not limited to, albumin, immunoglobulin --- including IgA, lipoprotein, apolipoprotein B, acid seromucoid, the huge balls of β -2- Albumen, thyroglobulin, transferrins, fibronectin, the VII factors, the VIII factors, the IX factors, the X factors and analog. In some embodiments, carrier protein is non-hematoglobin protein, such as casein, α-lactalbumin, beta lactoglobulin.Protein can With natural or be synthetically prepared.In some embodiments, protein is albumin, such as human albumin or human serum Albumin.In some embodiments, albumin is recombinant albumin.
Human serum albumins (HSA) is readily soluble globular protein Mr 65K, is made of 585 amino acid.HAS is blood plasma In most abundant protein, and occupy in human plasma the 70-80% of colloid osmotic pressure.The amino acid sequence of HAS includes altogether 17 disulphide bridges, a free sulfhydryl group (Cys 34) and single tryptophan (Trp 214).Intravenously shown using HSA solution Show for prevent and treat hypovolemic shock (see, e.g., Tullis, JAMA, 237,355-360,460-463, (1977)) and Houser et al., Surgery, Gynecology and Obstetrics, 150,811-816 (1980)) and Joint exchange transfusion is for treating newborn's (interior) hyperbilirubinemia disease (see, e.g., Finlayson, Seminars in Thrombosis and Hemostasis,6,85-120,(1980)).Consider other albumin, such as bovine serum albumin(BSA).It is this The application of non-human albumin can be appropriate, for example, (including domestic for non-human mammal such as animal doctor in these compositions Pet and agriculture situation) in the case of.Human serum albumins (HSA) has multiple hydrophobic binding sites, and (totally eight are used for fat Acid, the endogenous ligands of HAS) and combine various taxanes, especially neutral and electronegative hydrophobic compound (Goodman et al.,The Pharmacological Basis of Therapeutics,9th ed,McGraw-Hill New York (1996)).Two high affinity combined sites in the subdomain IIA and IIIA of HAS are had proposed, are the hydrophobic of extended height Bag, and surface nearby has the lysine and arginine residues of electrification, serves as the attachment point of polar ligand features (referring to example Such as, Fehske et al., Biochem.Pharmcol., 30,687-92 (198a), Vorum, Dan.Med.Bull., 46, 379-99(1999)、Kragh-Hansen,Dan.Med.Bull.,1441,131-40(1990)、Curry et al., Nat.Struct.Biol.,5,827-35(1998)、Sugio et al.,Protein.Eng.,12,439-46(1999)、He Et al., Nature, 358,209-15 (199b) and Carter et al., Adv.Protein.Chem., 45,153-203 (1994)).Have proven to taxol and propofol (propofol) combine HSA (see, e.g., Paal et al., Eur.J.Biochem.,268(7),2187-91(200a)、Purcell et al.,Biochim.Biophys.Acta,1478 (a), 61-8 (2000), Altmayer et al., Arzneimittelforschung, 45,1053-6 (1995) and Garrido et al.,Rev.Esp.Anestestiol.Reanim.,41,308-12(1994)).In addition, having proven to docetaxel (docetaxel) be bound to human plasma protein fraction matter (see, e.g., Urien et al., Invest.New Drugs, 14 (b), 147-51(1996))。
Carrier protein (for example, albumin, such as human albumin or human serum albumins) in composition generally acts as Japanese yew The carrier of alkane, that is, the albumin in composition makes taxane be easier to be suspended in compared with the composition for not including carrier protein Aqueous medium helps to maintain suspension.This can avoid using toxic solvent (or surfactant) to dissolve taxane, thus One or more side effects that taxane gives individual (such as people) can be reduced.Therefore, in some embodiments, as described herein Composition is substantially without (such as nothing) surfactant, such as Cremophor (or polyoxyethylated castor oil) (including Cremophor(BASF)).In some embodiments, Nanoparticulate compositions are substantially without (such as nothing) surfactant.If receiving Cremophor or amount of surfactant when rice grain composition is given individual in composition are not enough to cause one in individual Kind or a variety of side effects, then composition " substantially without Cremophor " or " substantially surfactant-free ".In some embodiment party In formula, Nanoparticulate compositions include less than about any of 20%, 15%, 10%, 7.5%, 5%, 2.5% or 1% Organic solvent or surfactant.In some embodiments, carrier protein is albumin.In some embodiments, white egg It is human albumin or human serum albumins in vain.In some embodiments, albumin is recombinant albumin.
Carrier protein (such as albumin) amount in composition as described herein will become according to the other components in composition Change.In some embodiments, the amount for the carrier protein such as albumin that composition includes is enough stable aqueous suspension (for example, steady Determine soliquid form (stable suspension of such as nano particle)) in taxane.In some embodiments, carrier protein As the amount of albumin reduces the sedimentation rate of taxane in an aqueous medium.About the composition comprising particle, carrier protein is for example white The amount of albumen additionally depends on the size and density of taxane nano particle.
If taxane it is long-term (such as at least about 0.1,0.2,0.25,0.5,1,2,3,4,5,6,7,8,9,10,11,12, 24, any of 36,48,60 or 72 hours) remain suspended in aqueous medium (e.g., no visible precipitate or or sedimentation), then Taxane is by " stabilization " in aqueous suspension.Suspension is usually but not necessarily suitable for administration to individual (such as people).Usually (but differ It is fixed) stability of evaluation suspension under storage temperature (such as room temperature (such as 20-25 DEG C) or refrigerated condition (such as 4 DEG C)).For example, such as The visible flocculation when about 15 minutes are not presented bore hole or 1000 times of optical microphotograph microscopic observations after suspension is made of fruit suspension liquid Or particle agglomeration, then suspension stablize at the storage temperature.Stability can also be evaluated under the conditions of accelerated test, such as in height In about 40 DEG C of temperature.
In some embodiments, the amount of carrier protein (for example, albumin) is enough certain in stabilized aqueous suspension The taxane of a concentration.For example, the taxane concentration in composition is about 0.1 to about 100mg/ml, including, for example, about 0.1 to About 50mg/ml, about 0.1 to about 20mg/ml, about 1 to about 10mg/ml, about 2mg/ml to about 8mg/ml, about 4 to about 6mg/ml or About any of 5mg/ml.In some embodiments, a concentration of at least about 1.3mg/ml, 1.5mg/ml of taxane, 2mg/ml、3mg/ml、4mg/ml、5mg/ml、6mg/ml、7mg/ml、8mg/ml、9mg/ml、10mg/ml、15mg/ml、20mg/ Any of ml, 25mg/ml, 30mg/ml, 40mg/ml and 50mg/ml.In some embodiments, carrier protein (for example, Albumin) amount avoid use surfactant (such as Cremophor) so that composition is free or substantially free of surface-active Agent (such as Cremophor).
In some embodiments, the composition of liquid form includes about 0.1% to about 50% (w/v) (for example, about 0.5% (w/v), about 5% (w/v), about 10% (w/v), about 15% (w/v), about 20% (w/v), about 30% (w/v), about 40% (w/v) Or about 50% (w/v)) carrier protein (for example, albumin).In some embodiments, the composition of liquid form includes about The carrier protein (for example, albumin) of 0.5% to about 5% (w/v).
In some embodiments, in Nanoparticulate compositions carrier protein (for example, albumin) and taxane weight Than making enough taxanes be incorporated into cell or by cell delivery.Although the weight of carrier protein (for example, albumin) and taxane Amount is optimized than that must be directed to different carrier proteins (for example, albumin) and taxane combination, but usually carrier protein (example Such as, albumin) with the weight ratio (w/w) of taxane it is about 0.01：1 to about 100：1, about 0.02：1 to about 50：1, about 0.05：1 To about 20：1, about 0.1：1 to about 20：1, about 1：1 to about 18：1, about 2：1 to about 15：1, about 3：1 to about 12：1, about 4：1 to about 10：1, about 5：1 to about 9：1 or about 9：1.In some embodiments, the weight of carrier protein (for example, albumin) and taxane Than being about 18：1 or smaller, 15：1 or smaller, 14：1 or smaller, 13：1 or smaller, 12：1 or smaller, 11：1 or smaller, 10：1 Or smaller, 9：1 or smaller, 8：1 or smaller, 7：1 or smaller, 6：1 or smaller, 5：1 or smaller, 4：1 or smaller and 3：1 or more It is any of small.In some embodiments, carrier protein is albumin.In some embodiments, white egg in composition The weight ratio of (such as human albumin or human serum albumins) and taxane is any of following in vain：About 1：1 to about 18：1, about 1：1 to about 15：1, about 1：1 to about 12：1, about 1：1 to about 10：1, about 1：1 to about 9：1, about 1：1 to about 8：1, about 1：1 to about 7： 1, about 1：1 to about 6：1, about 1：1 to about 5：1, about 1：1 to about 4：1, about 1：1 to about 3：1, about 1：1 to about 2：1, about 1：1 to about 1：1.
In some embodiments, carrier protein (for example, albumin) allows composition without notable side effect the case where Under be given individual (such as people).In some embodiments, carrier protein is (for example, albumin, as human serum albumins or people are white Albumen) amount effectively reduce one or more side effects that taxane gives people.Term " reduces one kind or more that taxane is given Kind side effect ", which refers to, reduces, mitigates, eliminates or avoids one or more undesirable effects caused by taxane, and is used for Deliver side effect caused by the delivery vector (as made taxane be suitable for the solvent of injection) of taxane.This side effect includes example Such as, bone marrow suppression, neurotoxicity, hypersensibility, inflammation, venous stimulation, phlebitis, pain, skin irritatin, peripheral nerve disease, in Property granulocyte reduce heat pyrexia, allergic reaction, phlebothrombosis, extravasation, and combinations thereof.However, these side effects are exemplary , and can reduce and be combined with other relevant side effects of taxane or side effect.
In some embodiments, Nanoparticulate compositions as described herein are including containing taxane (such as taxol) and in vain The nano particle of albumen (such as human albumin or human serum albumins), wherein nano particle have being averaged no more than about 200nm Diameter.In some embodiments, Nanoparticulate compositions as described herein include containing taxane (such as taxol) and white egg The nano particle of (such as human albumin or human serum albumins) in vain, wherein nano particle have average straight no more than about 150nm Diameter.In some embodiments, Nanoparticulate compositions as described herein include containing taxane (such as taxol) and albumin The nano particle of (such as human albumin or human serum albumins), wherein nano particle have the average diameter of about 130nm.At some In embodiment, Nanoparticulate compositions as described herein include containing taxol and human albumin (such as human serum albumins) Nano particle, wherein nano particle have the average diameter of about 130nm.
In some embodiments, Nanoparticulate compositions as described herein are including containing taxane (such as taxol) and in vain The nano particle of albumen (such as human albumin or human serum albumins), wherein nano particle have being averaged no more than about 200nm Diameter, the weight ratio of albumin and taxane is not greater than about 9 wherein in composition：1 (such as from about 9：1).In some embodiments, Nanoparticulate compositions as described herein include containing taxane (such as taxol) and albumin (such as human albumin or human seralbumin Albumen) nano particle, wherein nano particle have no more than about 150nm average diameter, wherein in composition albumin with The weight ratio of taxane is not greater than about 9：1 (such as from about 9：1).In some embodiments, Nanoparticulate compositions as described herein Nano particle including containing taxane (such as taxol) and albumin (such as human albumin or human serum albumins), wherein nanometer Particle has the average diameter of about 150nm, and the weight ratio of albumin and taxane is not greater than about 9 wherein in composition：1 (such as from about 9：1).In some embodiments, Nanoparticulate compositions as described herein include containing taxol and human albumin (such as people's blood Pure albumen) nano particle, wherein nano particle has the average diameter of about 130nm, wherein in composition albumin with it is purple The weight ratio of China fir alkane is about 9：1.
In some embodiments, Nanoparticulate compositions as described herein include nano particle, which includes It is coated with the taxane (such as taxol) of albumin (such as human albumin or human serum albumins).In some embodiments, originally Nanoparticulate compositions described in text include nano particle, which is coated with albumin (such as human albumin or people Seralbumin) taxane (such as taxol), wherein nano particle have no more than about 200nm average diameter.At some In embodiment, Nanoparticulate compositions as described herein include nano particle, which is coated with albumin (such as Human albumin or human serum albumins) taxane (such as taxol), wherein nano particle has being averaged no more than about 150nm Diameter.In some embodiments, Nanoparticulate compositions as described herein include nano particle, which includes coating There are the taxane (such as taxol) of albumin (such as human albumin or human serum albumins), wherein nano particle that there is about 130nm Average diameter.In some embodiments, Nanoparticulate compositions as described herein include nano particle, the nano particle packet The taxol for being coated with human albumin (such as human serum albumins) is included, wherein nano particle has the average diameter of about 130nm.
In some embodiments, Nanoparticulate compositions as described herein include nano particle, which includes Be coated with the taxane (such as taxol) of albumin (such as human albumin or human serum albumins), wherein in composition albumin with The weight ratio of taxane is not greater than about 9：1 (such as from about 9：1).In some embodiments, Nanoparticulate compositions as described herein Including nano particle, which is coated with the taxane of albumin (such as human albumin or human serum albumins) (such as Taxol), wherein nano particle has the average diameter no more than about 200nm, albumin and taxane wherein in composition Weight ratio is not greater than about 9：1 (such as from about 9：1).In some embodiments, Nanoparticulate compositions as described herein include nanometer Particle, the nano particle are coated with the taxane (such as taxol) of albumin (such as human albumin or human serum albumins), Wherein nano particle has the average diameter no more than about 150nm, and the weight ratio of albumin and taxane is not wherein in composition Greater than about 9：1 (such as from about 9：1).In some embodiments, Nanoparticulate compositions as described herein include nano particle, this is received Rice grain is coated with the taxane (such as taxol) of albumin (such as human albumin or human serum albumins), wherein nanometer Grain has the average diameter of about 150nm, and the weight ratio of albumin and taxane is not greater than about 9 wherein in composition：1 (such as from about 9： 1).In some embodiments, Nanoparticulate compositions as described herein include nano particle, which is coated with The taxol of human albumin (such as human serum albumins), wherein nano particle have the average diameter of about 130nm, wherein composition The weight ratio of middle albumin and taxane is about 9：1.
In some embodiments, Nanoparticulate compositions as described herein include nano particle, which includes The taxane (such as taxol) stablized by albumin (such as human albumin or human serum albumins).In some embodiments, originally Nanoparticulate compositions described in text include nano particle, which includes by albumin (such as human albumin or human serum Albumin) stablize taxane (such as taxol), wherein nano particle have no more than about 200nm average diameter.At some In embodiment, Nanoparticulate compositions as described herein include nano particle, which includes that (such as people is white by albumin Albumen or human serum albumins) taxane (such as taxol) stablized, wherein nano particle has being averaged no more than about 150nm Diameter.In some embodiments, Nanoparticulate compositions as described herein include nano particle, which includes by white The taxane (such as taxol) that albumen (such as human albumin or human serum albumins) is stablized, wherein nano particle have about 130nm Average diameter.In some embodiments, Nanoparticulate compositions as described herein include nano particle, the nano particle packet The taxol stablized by human albumin (such as human serum albumins) is included, wherein nano particle has the average diameter of about 130nm.
In some embodiments, Nanoparticulate compositions as described herein include nano particle, which includes By albumin (such as human albumin or human serum albumins) stablize taxane (such as taxol), wherein in composition albumin with The weight ratio of taxane is not greater than about 9：1 (such as from about 9：1).In some embodiments, Nanoparticulate compositions as described herein Including nano particle, the nano particle include by albumin (such as human albumin or human serum albumins) stablize taxane (such as Taxol), wherein nano particle has the average diameter no more than about 200nm, albumin and taxane wherein in composition Weight ratio is not greater than about 9：1 (such as from about 9：1).In some embodiments, Nanoparticulate compositions as described herein include nanometer Particle, the nano particle include the taxane (such as taxol) stablized by albumin (such as human albumin or human serum albumins), Wherein nano particle has the average diameter no more than about 150nm, and the weight ratio of albumin and taxane is not wherein in composition Greater than about 9：1 (such as from about 9：1).In some embodiments, Nanoparticulate compositions as described herein include nano particle, this is received Rice grain includes the taxane (such as taxol) stablized by albumin (such as human albumin or human serum albumins), wherein nanometer Grain has the average diameter of about 150nm, and the weight ratio of albumin and taxane is not greater than about 9 wherein in composition：1 (such as from about 9： 1).In some embodiments, Nanoparticulate compositions as described herein include nano particle, which includes white by people The taxol that albumen (such as human serum albumins) is stablized, wherein nano particle have the average diameter of about 130nm, wherein composition The weight ratio of middle albumin and taxane is about 9：1.
In some embodiments, Nanoparticulate compositions include Nab- taxols (or).In some implementations In mode, Nanoparticulate compositions be Nab- taxols (or)。Stablized by human albumin USP The preparation of taxol, being dispersed in can be in the physiological solution of direct injection.The weight ratio of human albumin and taxol is about 9： 1.When being dispersed in aqueous medium appropriate such as 0.9% sodium chloride injection or 5% glucose injection, Nab- taxols (or) formed taxol stable colloid suspension.The average particle size particle size of nano particle is in soliquid About 130 nanometers.Since HAS is soluble easily in water, Nab- taxols (or) can be extremely dense at dilute (0.1mg/ml taxols) It is reconstructed under the wide range of concentrations of (20mg/ml taxols), including, for example, about 2mg/ml to about 8mg/ml or about 5mg/ml.
The method for preparing Nanoparticulate compositions is known in the art.For example, including taxane (such as taxol) and carrier The nanometer of albumen (for example, albumin, such as human serum albumins or human albumin) can be in high-shear conditions (for example, at sound Reason, high-pressure homogeneous or conditions of similarity) under prepare.These methods are disclosed, for example, U.S. Patent number 5,916,596；6,506, 405；6,749,868,6,537,579 and 7,820,788；With U.S. Patent Publication No. 2007/0082838,2006/0263434 With PCT application WO08/137148.
In brief, taxane (such as taxol) is dissolved in organic solvent, and carrier protein solution can be added in solution, Such as albumin solution.Mixture is carried out high-pressure homogeneous.Then it can pass through evaporative removal organic solvent.The dispersion liquid of acquisition can quilt Further freeze-drying.Organic solvent appropriate includes, for example, ketone, ester, ether, chlorinated solvents and other solvents known in the art.Example Such as, organic solvent can be dichloromethane or chloroform/ethanol (for example, ratio is 1：9,1：8,1：7,1：6,1：5、1：4、1：3、 1：2、1：1、2：1、3：1、4：1、5：1、6：1、7：1、8：1 or 9：1).
Other components in Nanoparticulate compositions
Nano particle as described herein may be present in the composition for including other agent, excipient or stabilizer.For example, being logical It crosses and increases the negative zeta potential of nano particle to increase stability, one or more negatively charged components can be added.This negatively charged group Divide includes but not limited to by glycocholic acid, cholic acid, chenodeoxycholic acid, taurocholate, sweet ammonia chenodeoxycholic acid, ox sulphur chenodeoxycholic The bile salt of acid, lithocholic acid, ursodesoxycholic acid, dehydrocholic acid and other bile acids formed；Phosphatide, including lecithin (ovum It is yellow) it is phosphatide, including following phosphatidyl choline：Palmitoyloleoyl phosphatidyl choline, palmityl sub-oleoyl phosphatidyl choline, Stearoyl sub-oleoyl phosphatidyl choline, stearoyl oleolyl phosphatidyl choline, stearoyl peanut phosphatidyl choline and two Palmitoylphosphatidyl choline.Other phosphatide include L- α-dimyristoyl phosphatidyl choline (DMPC), dioleoyl phosphatidyl courage Alkali (DOPC), Distearoyl Phosphatidylcholine (DSPC), Hydrogenated Soybean Phosphatidylcholine (HSPC) and other related compounds.Band Electronegative surface activating agent or emulsifier also are suitable as additive, for example, cholesteryl sodium sulphate and analog.
In some embodiments, composition is suitable for administration to people.In some embodiments, composition is suitable for administration to lactation Animal, e.g., in animal doctor, domestic pets and agricultural animal.There are many Nanoparticulate compositions preparation appropriate (referring to, For example, U.S. Patent number 5,916,596,6,096,331 and 7,820,788).Lower series preparation and method are only exemplary, absolutely It is non-limiting.It can be made of following suitable for the oral preparation given：(a) liquid solution, be such as dissolved in diluent such as water, brine or A effective amount of compound in orange juice；(b) capsule, wafer or tablet include the active constituent of predetermined amount, as solid or Grain；(c) suspension in appropriate liquid；(d) lotion appropriate.Tablet form may include following one or more：It is lactose, sweet Reveal alcohol, cornstarch, potato starch, microcrystalline cellulose, Arabic gum, gelatin, colloidal silicon dioxide, cross-linked carboxymethyl fiber Plain sodium, talcum, magnesium stearate, stearic acid and other excipient, colorant, diluent, buffer, humidizer, preservative, seasoning Agent and the compatible excipient of pharmacology.Lozenge form may include in flavoring agent (usually sucrose and Arabic gum or bassora gum) Active constituent, and in inertial base (such as gelatin and glycerine or sucrose and Arabic gum) include the soft ingot of active constituent Agent, lotion, gel and the analog for also including excipient known in the art in addition to the active ingredient (s.
The example of carrier appropriate, excipient and diluent includes but not limited to, lactose, glucose, sucrose, sorbierite, Mannitol, starch, Arabic gum, calcium phosphate, alginate, bassora gum, gelatin, calcium silicates, microcrystalline cellulose, polyvinyl pyrrole Alkanone, cellulose, water, saline solution, syrup, methylcellulose, methyl and propylhydroxy benzoate, talcum, magnesium stearate And mineral oil.Preparation can also comprise lubricant, wetting agent, emulsification and suspending agent, preservative, sweetener or flavoring agent.
Include aqueous and non-aqueous isotonic sterile injection solution suitable for the parenteral preparation given, may include anti-oxidant Agent, buffer, fungicide and make preparation can be with the solute of the blood compatibility of intended recipient；It suspends with aqueous and non-aqueous sterile Liquid may include suspending agent, solubilizer, thickener, stabilizer and preservative.Preparation can be held with unit dose or multi-dose sealing Device such as ampoule bottle and bottle are prepared for unit, and can be stored under the conditions of freeze-drying (freeze-dried/lyophilized), Injectable sterile liquid excipient only need to be added shortly before use, for example, water.Extemporaneous injection solutions and suspension can be by aforementioned classes It is prepared by aseptic powdery, particle and the tablet of type.It is preferred that injectable formulation.
In some embodiments, composition is formulated the pH ranges with about 4.5 to about 9.0, including, for example, following Any pH ranges：About 5.0 to about 8.0, about 6.5 to about 7.5 and about 6.5 to about 7.0.In some embodiments, composition PH is configured to not less than about 6, including, for example, any of not less than about 6.5,7 or 8 (such as from about 8).Also it can pass through addition Tension regulator (tonicity modifier) appropriate such as glycerine, keeps composition isotonic with blood.
Product, kit, composition and drug
The present invention also provides kit, drug, composition, unit dosage forms and the systems for any method as described herein Product.
The kit of the present invention includes one or more containers, which includes the Nanoparticulate compositions containing taxane (or unit dosage forms and/or product) and/or other agent (such as at least one other agent as described herein), and in some embodiments In, further comprise the operation instruction according to any method as described herein.Kit can further comprise suitable for treatment The selection of body describes.The explanation that the kit of the present invention provides is usually label or package insert (for example, what kit included Page) on written explanation, but machine readable explanation (for example, the explanation carried on stored disk or CD) is also acceptable 's.
For example, in some embodiments, kit includes composition, the composition includes containing taxane and carrier egg White nano particle (for example, albumin, such as human serum albumins or human albumin).In some embodiments, kit into One step includes giving Nanoparticulate compositions to treat the explanation of an autologous melanoma.For another example in some embodiments, reagent Box includes a) composition comprising containing taxane (for example, taxol) and carrier protein (for example, albumin, such as human seralbumin Albumen or human albumin) nano particle；B) a effective amount of at least one other agent as described herein.In some embodiments In, kit further comprises administering to Nanoparticulate compositions and other at least one agent to treat the explanation of an autologous melanoma. Nano particle and other agent may be present in the container of difference or in single container.For example, kit may include a kind of define Composition or two or more compositions --- one of which composition includes nano particle, a kind of composition includes it His agent.Illustrate to can be on package insert or packaging label.Treatment can be according to either method as described herein.
The kit of the present invention is in packaging appropriate.It is appropriate to include but not limited to, it is bottle, bottle, tank, soft Property packaging the Mylar or polybag of sealing (for example) and analog.Kit optionally provides other component, such as buffers Agent and illustrate information.Therefore the application also provides product comprising bottle (such as sealed vial), unit dose or unit dosage forms, Bottle, tank, flexible package and analog.
The explanation used about Nanoparticulate compositions generally includes dosage, medication schedule and administration about goal treatment The information of approach.Container can be unit dose, self-contained packaging (for example, multiple-unit container) or subunit's dosage.For example, can carry For comprising it is disclosed herein be enough it is long-term (such as one week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 Week, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months are any of longer) dosage that individual is effectively treated is provided Taxane (such as taxane) kit.Kit may also include taxane and pharmaceutical composition and the use of multiple-units dosage Illustrate, and packed with being enough storage and the amount used in pharmacy (for example, hospital pharmacy and synthesis pharmacy).
The drug, composition and unit dosage forms that can be used for methods described herein are also provided.In some embodiments, it provides Drug (or composition or unit dosage forms) for treating autologous melanoma comprising it is a effective amount of containing taxane (for example, purple China fir alcohol) and carrier protein (for example, albumin, such as human serum albumins or human albumin) nano particle.In some embodiment party In formula, being used for for the nano particle including containing taxane and carrier protein (for example, albumin, such as human serum albumins) is provided Combine the drug (or composition or unit dosage forms) of other agent treatment autologous melanoma.
Other illustrative embodiments
In some embodiments, there is melanoma (the pernicious melanocyte of such as metastatic melanoma or metastatic for the treatment of individual human Tumor) method, including give individual effective dose include containing taxol and albumin nano particle (as have be not greater than about The nano particle of the average particle size particle size of 200nm) composition.In some embodiments, there is treatment individual human the black pigment of skin The method of tumor (such as pernicious cutaneous melanoma of metastatic cutaneous melanoma such as metastatic), including give individual effective dose includes containing There is the combination of the nano particle (as having the nano particle of the average particle size particle size no more than about 200nm) of taxol and albumin Object.In some embodiments, the melanoma (such as metastatic melanoma or metastatic malignant melanoma) for having treatment individual human Method, including the composition of individual effective dose is given, the composition includes the nanometer containing the taxol for being coated with albumin Grain (as having the nano particle of the average particle size particle size no more than about 200nm, for example, Nab- taxols).In some embodiment party In formula, there is the method for the treatment of individual human cutaneous melanoma (such as pernicious cutaneous melanoma of metastatic cutaneous melanoma such as metastatic), Composition including giving individual effective dose, the composition include the nano particle containing the taxol for being coated with albumin (such as Nano particle with the average particle size particle size no more than about 200nm, for example, Nab- taxols).In some embodiments, There is the method for the treatment of individual human cutaneous melanoma (such as pernicious cutaneous melanoma of metastatic cutaneous melanoma such as metastatic), including quiet The Nab- taxols of (for example, being perfused through about 30-40 minutes) individual effective dose are given in arteries and veins (for example, about 5mg/ml Nab- Japanese yews Alcohol), the dosage of taxol is about 80 to about 200mg/m wherein in Nanoparticulate compositions2(including for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2).In some embodiments, there is treatment individual human cutaneous melanoma (such as metastatic the black pigment of skin The pernicious cutaneous melanoma of tumor such as metastatic) method, be included in the 1st, 8, the 15 day intravenous administration in every 28 day period --- it is logical Cross and be perfused through about 30-40 minutes --- the Nab- taxols (for example, about 5mg/ml Nab- taxols) of individual effective dose, wherein The dosage of taxol is about 150mg/m in Nanoparticulate compositions2.In some embodiments, there is treatment individual human skin black The method of plain tumor (such as pernicious cutaneous melanoma of metastatic cutaneous melanoma such as metastatic), be included in every 28 day period the 1st, 8, The Nab- taxols of individual effective dose are (for example, about 5mg/ for 15 days intravenous administrations --- by being perfused through about 30-40 minutes --- Ml Nab- taxols), the dosage of taxol is about 120mg/m wherein in Nanoparticulate compositions2.In some embodiments, The method for having treatment individual human cutaneous melanoma (such as pernicious cutaneous melanoma of metastatic cutaneous melanoma such as metastatic), is included in 1st, 8,15 day intravenous administration --- by being perfused through the about 30-40 minutes --- Nab- of individual effective dose in every 28 day period Taxol (for example, about 5mg/ml Nab- taxols), the dosage of taxol is about 90mg/m wherein in Nanoparticulate compositions2。 In some embodiments, treatment individual at least about 2 months, including, for example, at least about 3,4,5,6,7,8,9,10,11 or 12 Any of a month.In some embodiments, individual is without chemotherapy.In some embodiments, melanoma is the IV stages Melanoma.In some embodiments, individual has far-end transfer.In some embodiments, metastatic melanoma is in M1a ranks Section.In some embodiments, metastatic melanoma is in the M1b stages.In some embodiments, metastatic melanoma is in M1c Stage.In some embodiments, individual suffers from measurable disease.In some embodiments, individual has the melanocyte of brain metastes Tumor.In some embodiments, individual does not have brain metastes.In some embodiments, individual includes wild type BRAF.At some In embodiment, individual includes mutant BRAF (such as the BRAF with V600E mutation).In some embodiments, individual tool There is raised LDH horizontal.In some embodiments, individual is women.In some embodiments, individual about 65 years old with Under.In some embodiments, individual is at least about 65 years old (for example, any of at least about 70,75 or 80 years old).
In some embodiments, there is melanoma (the pernicious melanocyte of such as metastatic melanoma or metastatic for the treatment of individual human Tumor) method, wherein it is described individual before do not received for melanoma treatment or do not received preceding cytotoxicity Therapy, such as preceding auxiliary cell toxicity therapy are learned, including give individual effective dose includes containing taxol and albumin The composition of nano particle (as having the nano particle of the average particle size particle size no more than about 200nm).In some embodiments In, there is the method for the melanoma (such as metastatic melanoma or metastatic malignant melanoma) for the treatment of individual human, wherein the individual Do not received the treatment for melanoma before or do not received preceding cytotoxic chemotherapy, such as preceding auxiliary cell Toxicity therapy, including the composition of individual effective dose is given, the composition includes receiving containing the taxol for being coated with albumin Rice grain (as having the nano particle of the average particle size particle size no more than about 200nm, for example, Nab- taxols).In some realities It applies in mode, there is the method for the melanoma (such as metastatic melanoma or metastatic malignant melanoma) for the treatment of individual human, wherein institute Do not receive the treatment for melanoma before stating individual or does not receive preceding cytotoxic chemotherapy, it is such as preceding auxiliary Synergidae toxicity therapy includes the Nab- taxols of intravenous administration (for example, being perfused through about 30-40 minutes) individual effective dose (for example, about 5mg/ml Nab- taxols), the dosage of taxol is about 80 to about 200mg/m wherein in Nanoparticulate compositions2 (including for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2).In some embodiments, there is the black for the treatment of individual human The method of plain tumor (such as metastatic melanoma or metastatic malignant melanoma), wherein not receiving to be directed to melanocyte before the individual The treatment of tumor did not received preceding cytotoxic chemotherapy, such as preceding auxiliary cell toxicity therapy, was included in every 28 The the 1st, 8,15 day of its period (is such as perfused through about 30-40 minutes) by intravenous administration, intravenous administration individual effective dose Nab- taxols (for example, about 5mg/ml Nab- taxols), wherein in Nanoparticulate compositions the dosage of taxol be about 80 to About 200mg/m2(including for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2).In some embodiments, there is treatment The method of the melanoma (such as metastatic melanoma or metastatic malignant melanoma) of individual human, wherein not receiving before the individual It crosses the treatment for melanoma or did not received preceding cytotoxic chemotherapy, such as preceding auxiliary cell toxicity therapy, It is included in the 1st, 8, the 15 day intravenous administration in every 28 day period --- by being perfused through about 30-40 minutes --- individual effective dose Nab- taxols (for example, about 5mg/ml Nab- taxols), wherein the dosage of taxol is about in Nanoparticulate compositions 150mg/m2.In some embodiments, there is melanoma (the pernicious melanocyte of such as metastatic melanoma or metastatic for the treatment of individual human Tumor) method, wherein it is described individual before do not received for melanoma treatment or do not received preceding cytotoxicity Therapy, such as preceding auxiliary cell toxicity therapy are learned, the 1st, 8, the 15 day intravenous administration in every 28 day period is included in --- it is logical Cross and be perfused through about 30-40 minutes --- the Nab- taxols (for example, about 5mg/ml Nab- taxols) of individual effective dose, wherein The dosage of taxol is about 120mg/m in Nanoparticulate compositions2.In some embodiments, there is the melanocyte for the treatment of individual human The method of tumor (such as metastatic melanoma or metastatic malignant melanoma), wherein not receiving to be directed to melanoma before the individual Treatment or do not received preceding cytotoxic chemotherapy, such as preceding auxiliary cell toxicity therapy, be included in every 28 days 1st, 8,15 day intravenous administration --- by being perfused through about 30-40 minutes --- the Nab- taxols of individual effective dose in period (for example, about 5mg/ml Nab- taxols), the dosage of taxol is about 90mg/m wherein in Nanoparticulate compositions2.At some In embodiment, treatment individual at least about 2 months, including, for example, at least about 3,4,5,6,7,8,9,10,11 or 12 middle of the month Any one.In some embodiments, melanoma is IV stage melanoma.In some embodiments, individual has far-end transfer. In some embodiments, metastatic melanoma is in the M1a stages.In some embodiments, metastatic melanoma is in M1b ranks Section.In some embodiments, metastatic melanoma is in the M1c stages.In some embodiments, individual suffers from measurable disease Disease.In some embodiments, individual has the melanoma of brain metastes.In some embodiments, individual does not have brain metastes.One In a little embodiments, individual includes wild type BRAF.In some embodiments, individual, which includes mutant BRAF, (such as has The BRAF of V600E mutation).In some embodiments, individual has raised LDH horizontal.In some embodiments, individual It is women.In some embodiments, individual was at about 65 years old or less.In some embodiments, individual is at least about 65 years old (example Such as, at least about 70,75 or any of 80 years old).
In some embodiments, there is melanoma (the pernicious melanocyte of such as metastatic melanoma or metastatic for the treatment of individual human Tumor) method, wherein receiving the treatment for melanoma before the individual or receiving preceding cytotoxic chemical to treat Method, such as preceding auxiliary cell toxicity therapy, including give individual effective dose includes the nanometer containing taxol and albumin The composition of particle (as having the nano particle of the average particle size particle size no more than about 200nm).In some embodiments, have The method for treating the melanoma (such as metastatic melanoma or metastatic malignant melanoma) of individual human, wherein being connect before the individual It has received the treatment for melanoma or had received preceding cytotoxic chemotherapy, such as preceding auxiliary cell toxicity therapy, Composition including giving individual effective dose, the composition include the nano particle containing the taxol for being coated with albumin (such as Nano particle with the average particle size particle size no more than about 200nm, for example, Nab- taxols).In some embodiments, There is the method for the melanoma (such as metastatic melanoma or metastatic malignant melanoma) for the treatment of individual human, wherein before the individual Received the treatment for melanoma or received preceding cytotoxic chemotherapy, such as preceding auxiliary cell toxicity is treated Method, including intravenous administration (for example, through about 30-40 minutes be perfused) individual effective dose Nab- taxols (for example, about 5mg/ml Nab- taxols), the dosage of taxol is about 80 to about 200mg/m wherein in Nanoparticulate compositions2(including for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2).In some embodiments, there is melanoma (such as metastatic for the treatment of individual human Melanoma or metastatic malignant melanoma) method, wherein receiving the treatment or receiving for melanoma before the individual Preceding cytotoxic chemotherapy is crossed, such as preceding auxiliary cell toxicity therapy, is included in the 1st, 8, the 15 of every 28 day period The Nab- taxols of its intravenous administration (for example, being perfused through about 30-40 minutes) individual effective dose are (for example, about 5mg/ml Nab- Taxol), the dosage of taxol is about 80 to about 200mg/m wherein in Nanoparticulate compositions2(including for example, about 90mg/ m2, about 120mg/m2Or about 150mg/m2).In some embodiments, there is melanoma (such as metastatic melanocyte for the treatment of individual human Tumor or metastatic malignant melanoma) method, wherein it is described individual before received for melanoma treatment or received Preceding cytotoxic chemotherapy, such as preceding auxiliary cell toxicity therapy, be included in every 28 day period the 1st, 8,15 day pass through Perfusion is to the Nab- taxols (for example, about 5mg/ml Nab- taxols) of individual effective dose, wherein nanometer within about 30-40 minutes The dosage of taxol is about 150mg/m in grain composition2.In some embodiments, treatment individual at least about 2 months, including, For example, any of at least about 3,4,5,6,7,8,9,10,11 or 12 months.In some embodiments, there is treatment individual human Melanoma (such as metastatic melanoma or metastatic malignant melanoma) method, wherein receiving for black before the individual The treatment of plain tumor received preceding cytotoxic chemotherapy, such as preceding auxiliary cell toxicity therapy, was included in every 28 The Nab- taxols to individual effective dose were perfused (for example, about 5mg/ml through about 30-40 minutes in the 1st, 8,15 day of its period Nab- taxols), the dosage of taxol is about 120mg/m wherein in Nanoparticulate compositions2.In some embodiments, have The method for treating the melanoma (such as metastatic melanoma or metastatic malignant melanoma) of individual human, wherein being connect before the individual It has received the treatment for melanoma or had received preceding cytotoxic chemotherapy, such as preceding auxiliary cell toxicity therapy, The Nab- taxols to individual effective dose were perfused (for example, about through about 30-40 minutes in be included in every 28 day period the 1st, 8,15 day 5mg/ml Nab- taxols), the dosage of taxol is about 90mg/m wherein in Nanoparticulate compositions2.In some embodiments In, treatment individual at least about 2 months, including, for example, any of at least about 3,4,5,6,7,8,9,10,11 or 12 months. In some embodiments, melanoma is IV stage melanoma.In some embodiments, individual has far-end transfer.In some realities It applies in mode, metastatic melanoma is in the M1a stages.In some embodiments, metastatic melanoma is in the M1b stages.At some In embodiment, metastatic melanoma is in the M1c stages.In some embodiments, individual suffers from measurable disease.In some realities It applies in mode, individual has the melanoma of brain metastes.In some embodiments, individual does not have brain metastes.In some embodiments In, individual includes wild type BRAF.In some embodiments, individual includes mutant BRAF (as being mutated with V600E BRAF).In some embodiments, individual has raised LDH horizontal.In some embodiments, individual is women.One In a little embodiments, individual was at about 65 years old or less.In some embodiments, individual is at least about 65 years old (for example, at least about 70,75 or any of 80 years old).
In some embodiments, there is melanoma (the pernicious melanocyte of such as metastatic melanoma or metastatic for the treatment of individual human Tumor) method, wherein the individual has raised LDH horizontal, including give individual effective dose include containing taxol and The composition of the nano particle (as having the nano particle of the average particle size particle size no more than about 200nm) of albumin.At some In embodiment, there is the method for the melanoma (such as metastatic melanoma or metastatic malignant melanoma) for the treatment of individual human, wherein The individual has raised LDH levels, including gives the composition of individual effective dose, and the composition includes white containing being coated with The nano particle of the taxol of albumen is (as having the nano particle of the average particle size particle size no more than about 200nm, for example, Nab- Taxol).In some embodiments, there is melanoma (the pernicious melanocyte of such as metastatic melanoma or metastatic for the treatment of individual human Tumor) method, wherein the individual has raised LDH horizontal, including intravenous administration is (for example, through filling in about 30-40 minute Note) individual effective dose Nab- taxols (for example, about 5mg/ml Nab- taxols), wherein Japanese yew in Nanoparticulate compositions The dosage of alcohol is about 80 to about 200mg/m2(including for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2).At some In embodiment, there is the method for the melanoma (such as metastatic melanoma or metastatic malignant melanoma) for the treatment of individual human, wherein The individual has raised LDH horizontal, is included in the 1st, 8, the 15 day intravenous administration in every 28 day period (for example, through about 30- It is perfused within 40 minutes) the Nab- taxols (for example, about 5mg/ml Nab- taxols) of individual effective dose, wherein nano particle combines The dosage of taxol is about 80 to about 200mg/m in object2(including for example, about 90mg/m2, about 120mg/m2Or about 150mg/ m2).In some embodiments, the melanoma (such as metastatic melanoma or metastatic malignant melanoma) for having treatment individual human Method is included in the 1st, 8,15 day of every 28 day period through about 30-40 minutes wherein the individual has raised LDH horizontal It is perfused and gives the Nab- taxols of individual effective dose (for example, about 5mg/ml Nab- taxols), it is purple wherein in Nanoparticulate compositions The dosage of China fir alcohol is about 150mg/m2.In some embodiments, have treatment individual human melanoma (such as metastatic melanoma or Metastatic malignant melanoma) method, wherein the individual has raised LDH horizontal, be included in every 28 day period the 1st, 8, it was perfused to the Nab- taxols (for example, about 5mg/ml Nab- taxols) of individual effective dose through about 30-40 minutes within 15 days, The dosage of taxol is about 120mg/m in middle Nanoparticulate compositions2.In some embodiments, there is the black for the treatment of individual human The method of plain tumor (such as metastatic melanoma or metastatic malignant melanoma), wherein the individual has, raised LDH is horizontal, packet It includes and the Nab- taxols to individual effective dose was perfused (for example, about through about 30-40 minutes within the 1st, 8,15 day in every 28 day period 5mg/ml Nab- taxols), the dosage of taxol is about 90mg/m wherein in Nanoparticulate compositions2.In some embodiments In, treatment individual at least about 2 months, including, for example, any of at least about 3,4,5,6,7,8,9,10,11 or 12 months. In some embodiments, individual has about 0.8 × to the Serum LDH of about 1.1 × ULN.In some embodiments, individual has Greater than about 1.1 × to the Serum LDH between about 2.0 × ULN.In some embodiments, individual includes wild type BRAF.One In a little embodiments, individual includes mutant BRAF (such as the BRAF with V600E mutation).In some embodiments, individual With M1c stage metastatic melanomas.In some embodiments, individual is women.In some embodiments, individual is about 65 years old or less.In some embodiments, individual is at least about 65 years old (for example, any of at least about 70,75 or 80 years old).
In some embodiments, there is melanoma (the pernicious melanocyte of such as metastatic melanoma or metastatic for the treatment of individual human Tumor) method, wherein it is described individual include wild type BRAF, including give individual effective dose include contain taxol and white egg The composition of white nano particle (as having the nano particle of the average particle size particle size no more than about 200nm).In some implementations In mode, there is the method for the melanoma (such as metastatic melanoma or metastatic malignant melanoma) for the treatment of individual human, wherein described Individual includes wild type BRAF, including gives the composition of individual effective dose, and the composition includes containing being coated with albumin The nano particle of taxol is (as having the nano particle of the average particle size particle size no more than about 200nm, for example, Nab- Japanese yews Alcohol).In some embodiments, the melanoma (such as metastatic melanoma or metastatic malignant melanoma) for having treatment individual human Method, wherein the individual includes wild type BRAF, including intravenous administration (for example, being perfused through about 30-40 minutes) individual has The Nab- taxols (for example, about 5mg/ml Nab- taxols) of effect amount, wherein the dosage of taxol is in Nanoparticulate compositions About 80 to about 200mg/m2(including for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2).In some embodiments, The method for having the melanoma (such as metastatic melanoma or metastatic malignant melanoma) for the treatment of individual human, wherein the individual includes Wild type BRAF is included in the 1st, 8,15 day intravenous administration (for example, being perfused through the about 30-40 minutes) individual in every 28 day period A effective amount of Nab- taxols (for example, about 5mg/ml Nab- taxols), the dosage of taxol wherein in Nanoparticulate compositions It is about 80 to about 200mg/m2(including for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2).In some embodiments In, there is the method for the melanoma (such as metastatic melanoma or metastatic malignant melanoma) for the treatment of individual human, wherein the individual Including wild type BRAF, be included in every 28 day period the 1st, 8,15 day was perfused through about 30-40 minutes to individual effective dose Nab- taxols (for example, about 5mg/ml Nab- taxols), wherein the dosage of taxol is about in Nanoparticulate compositions 150mg/m2.In some embodiments, there is melanoma (the pernicious melanocyte of such as metastatic melanoma or metastatic for the treatment of individual human Tumor) method be included in the 1st, 8,15 day of every 28 day period through about 30-40 points wherein the individual includes wild type BRAF Clock, which is perfused, gives the Nab- taxols of individual effective dose (for example, about 5mg/ml Nab- taxols), wherein in Nanoparticulate compositions The dosage of taxol is about 120mg/m2.In some embodiments, there is melanoma (such as metastatic melanoma for the treatment of individual human Or metastatic malignant melanoma) method, wherein it is described individual include wild type BRAF, be included in every 28 day period the 1st, 8, It was perfused to the Nab- taxols (for example, about 5mg/ml Nab- taxols) of individual effective dose through about 30-40 minutes within 15 days, wherein The dosage of taxol is about 90mg/m in Nanoparticulate compositions2.In some embodiments, treatment individual at least about 2 months, Including for example, any of at least about 3,4,5,6,7,8,9,10,11 or 12 months.In some embodiments, individual has M1c stage melanoma.In some embodiments, individual has raised LDH horizontal.In some embodiments, individual is Women.In some embodiments, individual was at about 65 years old or less.In some embodiments, individual is at least about 65 years old (example Such as, at least about 70,75 or any of 80 years old).
In some embodiments, there is melanoma (the pernicious melanocyte of such as metastatic melanoma or metastatic for the treatment of individual human Tumor) method, wherein the individual includes the mutation (such as V600E mutation) of BRAF, including give individual effective dose includes containing There is the combination of the nano particle (as having the nano particle of the average particle size particle size no more than about 200nm) of taxol and albumin Object.In some embodiments, the melanoma (such as metastatic melanoma or metastatic malignant melanoma) for having treatment individual human Method wherein the individual includes the mutation (such as V600E mutation) of BRAF, including gives the composition of individual effective dose, the group Conjunction object includes the nano particle containing the taxol for being coated with albumin (as having the average particle size particle size no more than about 200nm Nano particle, for example, Nab- taxols).In some embodiments, have treatment individual human melanoma (such as metastatic is black Plain tumor or metastatic malignant melanoma) method, wherein the individual includes the mutation (such as V600E mutation) of BRAF, including quiet The Nab- taxols of (for example, being perfused through about 30-40 minutes) individual effective dose are given in arteries and veins (for example, about 5mg/ml Nab- Japanese yews Alcohol), the dosage of taxol is about 80 to about 200mg/m wherein in Nanoparticulate compositions2(including for example, about 90mg/m2, about 120mg/m2Or about 150mg/m2).In some embodiments, have treatment individual human melanoma (such as metastatic melanoma or turn Move property chromoma) method be included in every 28 day week wherein the individual includes the mutation (such as V600E mutation) of BRAF The the 1st, 8,15 day intravenous administration (for example, through about 30-40 minutes be perfused) individual effective dose of phase Nab- taxols (for example, About 5mg/ml Nab- taxols), the dosage of taxol is about 80 to about 200mg/m wherein in Nanoparticulate compositions2(including For example, about 90mg/m2, about 120mg/m2Or about 150mg/m2).In some embodiments, there is the melanoma for the treatment of individual human The method of (such as metastatic melanoma or metastatic malignant melanoma), wherein (such as V600E is prominent for mutation of the individual including BRAF Become), it is included in the 1st, 8, the 15 day Nab- taxol (example through perfusion in about 30-40 minutes to individual effective dose in every 28 day period Such as, about 5mg/ml Nab- taxols), the dosage of taxol is about 150mg/m wherein in Nanoparticulate compositions2.In some realities It applies in mode, there is the method for the melanoma (such as metastatic melanoma or metastatic malignant melanoma) for the treatment of individual human, wherein institute The mutation (such as V600E mutation) that individual includes BRAF is stated, be included in every 28 day period the 1st, 8,15 day was filled through about 30-40 minutes It notes and gives the Nab- taxols of individual effective dose (for example, about 5mg/ml Nab- taxols), wherein Japanese yew in Nanoparticulate compositions The dosage of alcohol is about 120mg/m2.In some embodiments, have treatment individual human melanoma (such as metastatic melanoma or turn Move property chromoma) method be included in every 28 day week wherein the individual includes the mutation (such as V600E mutation) of BRAF The the 1st, 8,15 day of phase was perfused to the Nab- taxols of individual effective dose through about 30-40 minutes (for example, about 5mg/ml Nab- are purple China fir alcohol), the dosage of taxol is about 90mg/m wherein in Nanoparticulate compositions2.In some embodiments, treatment is individual extremely It is about 2 months few, including, for example, any of at least about 3,4,5,6,7,8,9,10,11 or 12 months.In some embodiments In, individual has M1c stage melanoma.In some embodiments, individual has raised LDH horizontal.In some embodiment party In formula, individual is women.In some embodiments, individual was at about 65 years old or less.In some embodiments, individual is at least About 65 years old (for example, any of at least about 70,75 or 80 years old).
Include the nano particle containing taxol and albumin in some embodiments of any method described herein Composition is as monotherapy for treating melanoma.
Combination therapy is also provided herein, including following：Treatment including giving Nanoparticulate compositions as described herein Method and the second therapy.In some embodiments, the second therapy is selected from chemotherapy, immunotherapy, operation, radiotherapy, target To therapy or combinations thereof.In some embodiments, method includes giving at least one other therapeutic agents.In some embodiments In, other therapeutic agents are BRAF inhibitor.In some embodiments, other therapeutic agents are her wooden monoclonal antibodies.In some implementations In mode, this method is used as the first gamma therapy.In some embodiments, this method is used as the second gamma therapy.Described herein In some embodiments of any method, including contain taxane (for example, taxol) and carrier protein (for example, albumin) The composition of nano particle is by intravenous administration.In some embodiments, the taxane in Nanoparticulate compositions (for example, Taxol) amount (dosage) be about 50mg/m2To about 400mg/m2.In some embodiments, the Japanese yew in Nanoparticulate compositions It is about 100mg/m that alkane (for example, taxol), which measures (dosage),2To about 200mg/m2.In some embodiments, nano particle combines Taxane (for example, taxol) amount (dosage) in object is about 150mg/m2.In some embodiments, including contain taxane The composition of the nano particle of (for example, taxol) and carrier protein (for example, albumin) is given weekly.In some embodiment party In formula, method includes at least one 28 days treatment cycles.In some embodiments, including contain taxane (for example, Japanese yew Alcohol) and carrier protein (for example, albumin) nano particle composition the 1st, 8 and 15 day of 28 days treatment cycles by It gives.
In some embodiments, albumin is human serum albumins.In some embodiments, albumin is the white egg of people In vain.In some embodiments, albumin is recombinant albumin.In some embodiments, in composition nano particle it is flat Equal diameter is not greater than about 200nm.In some embodiments, in Nanoparticulate compositions albumin and taxane (for example, Japanese yew Alcohol) weight ratio be about 9：1 or smaller.In some embodiments, albumin and taxane (example in Nanoparticulate compositions Such as, taxol) weight ratio be about 9：1.In some embodiments, the taxane in nano particle (for example, taxol) wraps There is albumin.In some embodiments, taxane is taxol.In some embodiments, provide treatment individual (example Such as, people) melanoma method, including give individual effective dose include containing taxol and albumin (for example, human albumin or Human serum albumins) nano particle composition.
The method that the application provides treatment individual human melanoma in some embodiments, including give individual effective dose It include the composition of the nano particle containing taxol and albumin.
In some embodiments according to (or being applicable in) any of the above described embodiment, melanoma is cutaneous melanoma.
In some embodiments according to (or being applicable in) any of the above described embodiment, melanoma is metastatic melanoma.
In some embodiments according to (or being applicable in) any of the above described embodiment, melanoma is the pernicious melanocyte of metastatic Tumor.
In some embodiments according to (or being applicable in) any of the above described embodiment, melanoma is IV stage melanoma.
In some embodiments according to (or being applicable in) any of the above described embodiment, individual has far-end transfer.
In some embodiments according to (or being applicable in) any of the above described embodiment, metastatic melanoma is in the M1a stages.
In some embodiments according to (or being applicable in) any of the above described embodiment, metastatic melanoma is in the M1b stages.
In some embodiments according to (or being applicable in) any of the above described embodiment, metastatic melanoma is in the M1c stages.
In some embodiments according to (or being applicable in) any of the above described embodiment, individual suffers from measurable disease.
In some embodiments according to (or being applicable in) any of the above described embodiment, individual does not have brain metastes.
In some embodiments according to (or being applicable in) any of the above described embodiment, do not received before individual for black The treatment of plain tumor.
In some embodiments according to (or being applicable in) any of the above described embodiment, individual did not received preceding be directed to The cytotoxic chemotherapy of metastatic malignant melanoma.
In some embodiments according to (or being applicable in) any of the above described embodiment, individual did not received preceding auxiliary Cytotoxic chemotherapy.
In some embodiments according to (or being applicable in) any of the above described embodiment, individual is male.
In some embodiments according to (or being applicable in) any of the above described embodiment, individual is women.
In some embodiments according to (or being applicable in) any of the above described embodiment, individual was at about 65 years old or less.
In some embodiments according to (or be applicable in) any of the above described embodiment, individual at least about 65 years old (for example, At least about 70,75 or any of 80 years old).
In some embodiments according to (or being applicable in) any of the above described embodiment, individual has raised serum lactic Dehydrogenase (" LDH ") is horizontal.
In some embodiments according to (or be applicable in) any of the above described embodiment, individual have be less than about 0.8 × just The Serum LDH of constant value lower limit (" ULN ").
In some embodiments according to (or be applicable in) any of the above described embodiment, individual has about 0.8 × to about 1.1 The Serum LDH of × ULN.
In some embodiments according to (or be applicable in) any of the above described embodiment, individual has greater than about 1.1 × extremely Serum LDH between about 2.0 × ULN.
In some embodiments according to (or being applicable in) any of the above described embodiment, melanoma includes wild type BRAF.
In some embodiments according to (or being applicable in) any of the above described embodiment, melanoma includes the mutation of BRAF.
In some embodiments according to (or being applicable in) any of the above described embodiment, melanoma includes in BRAF V600E is mutated.
In some embodiments according to (or being applicable in) any of the above described embodiment, including contain taxol and albumin Nano particle composition as monotherapy for treating melanoma.
In some embodiments according to (or being applicable in) any of the above described embodiment, method further comprises the second treatment Method.
In some embodiments according to (or be applicable in) any of the above described embodiment, the second therapy be selected from chemotherapy, Immunotherapy, operation, radiotherapy, targeted therapies or combinations thereof.
In some embodiments according to (or being applicable in) any of the above described embodiment, method further comprises administering at least A kind of other therapeutic agents.
In some embodiments according to (or being applicable in) any of the above described embodiment, other therapeutic agents are that BRAF inhibits Agent.
In some embodiments according to (or being applicable in) any of the above described embodiment, other therapeutic agents are that her wood is single It is anti-.
In some embodiments according to (or being applicable in) any of the above described embodiment, this method is used as the first gamma therapy.
In some embodiments according to (or being applicable in) any of the above described embodiment, this method is used as the second gamma therapy.
In some embodiments according to (or being applicable in) any of the above described embodiment, including contain taxol and albumin Nano particle composition by intravenous administration.
In some embodiments according to (or being applicable in) any of the above described embodiment, taxol in Nanoparticulate compositions Dosage be about 50mg/m2To about 400mg/m2。
In some embodiments according to (or being applicable in) any of the above described embodiment, taxol in Nanoparticulate compositions Dosage be about 100mg/m2To about 200mg/m2。
In some embodiments according to (or being applicable in) any of the above described embodiment, taxol in Nanoparticulate compositions Dosage be about 150mg/m2。
In some embodiments according to (or being applicable in) any of the above described embodiment, including contain taxol and albumin The composition of nano particle given weekly.
In some embodiments according to (or being applicable in) any of the above described embodiment, method includes controlling at least one 28 days Treat the period.
In some embodiments according to (or being applicable in) any of the above described embodiment, including contain taxol and albumin Nano particle composition being given for the 1st, 8 and 15 day in 28 days treatment cycles.
In some embodiments according to (or being applicable in) any of the above described embodiment, albumin is human serum albumins.
In some embodiments according to (or being applicable in) any of the above described embodiment, albumin is human albumin.
In some embodiments according to (or being applicable in) any of the above described embodiment, albumin is recombinant albumin.
In some embodiments according to (or being applicable in) any of the above described embodiment, nano particle is averaged in composition Diameter is not greater than about 200nm.
In some embodiments according to (or being applicable in) any of the above described embodiment, albumin in Nanoparticulate compositions Weight ratio with taxol is about 9：1 or smaller.
In some embodiments according to (or being applicable in) any of the above described embodiment, albumin in Nanoparticulate compositions Weight ratio with taxol is about 9：1.
In some embodiments according to (or being applicable in) any of the above described embodiment, the taxol coating in nano particle There is albumin.
It will be understood by those skilled in the art that multiple embodiments may include within the scope and spirit of this invention.Now join Following non-limiting examples are examined the present invention is described in more detail.The further example present invention of the following example, but work as So it is not construed in any way as limiting its range.
Embodiment
Embodiment 1：Nab- taxols compare 3 phases of the Dacarbazine in the metastatic malignant melanoma patient without chemotherapy Research
IV stage cutaneous metastatic chromoma patient selections without chemotherapy.Patient has east tumour cooperative groups (ECOG) lactic dehydrogenase (LDH) of PS 0-1, measurable disease and≤2.0 × lower limits of normal (ULN) are horizontal, and do not have There are current brain metastes.Patient baseline's feature is shown in table 5.Patient is divided into two groups：(1) Nab- taxols (" Nab-P ",), 150mg/m2, intravenously, unmatched medication, at the 1st, 8 and 15 day of 28 day period；(2) Dacarbazine (DTIC), 1000mg/m2, intravenously, at the 1st day of 21 day period.Fig. 1 shows 3 phase research and designs.
5. baseline characteristic of table
Primary efficacy endpoint is based on blind Radiologic evaluations (according to the response evaluation criterion (" RECIST ") of entity tumor V1.0 progression free survival phase (" PFS ")).Secondary efficacy endpoint is Overall survival (" OS ").Other terminals include objective response Rate (" ORR "), disease control rate (" DCR ") and safety/tolerance.
The PFS results of Fig. 2 display researchs (PFS is checked by separate radiation and carried out).The plan mid-term of Fig. 3 display researchs The OS results of analysis.Other efficacy endpoints of research are shown in table 6.
Other efficacy endpoints of table 6.
* include the PR+SD+PD confirmed
P：Improve the ratio of patient；PD：Progressive disease；PR：Part responds；SD：Stable disease
The research PFS and mid-term OS carried out by BRAF states is analysis shows that in table 7.
The PFS and mid-term OS that table 7. passes through BRAF states
Fig. 4 shows the OS interim analysis of the subgroup based on various patient characteristics.Fig. 4 shows whether some subgroup is conducive to Nab- paclitaxel treatments (comparison DTIC treatments) and its degree.
The adverse events of research are shown in table 8.
8. >=5% patient of table >=3 grades of treatment-related adverse events (TRAE)
* except lymphocyte is reduced, all event P<0.05
* is entirely 3 grades other than 2 neuropathy events
The results show that this research reaches its PFS Primary endpoint：4.8 couples of 2.5 months (P=0.044, Nab- taxol vs Dacarbazine).Mid-term OS is analysis shows that support the trend of Nab- taxol groups.Other terminals (ORR, DCR) and subgroup show one The benefit of the weighting Nab- taxol groups of cause.Most significant AE was >=3 grades of neuropathy in Nab- taxol groups, at one month Inside improved.This research confirms that Nab- taxols are better than standard Dacarbazine chemotherapy.
Embodiment 2：Nab- taxols compare Dacarbazine and suffer from the metastatic malignant melanoma for not receiving treatment before 3 phases research in person
The main purpose of this research is to compare to investigate drug Nab- taxolsDacarbazine is compared at it Preceding safety, tolerance and the antitumor activity not received in chemotherapeutic metastatic melanoma patient.
Treatment group A：Receive the patients of Nab- taxols through about 30 minutes by intravenous administration, before no steroids medication and No G-CSF prevents (unless changing as described below)；150mg/m2, the 1st, 8 and 15 day of every 4 weeks.Treatment group B：Receiving reaches The patient of carbazine is on day 1 with 1000mg/m2Intravenous administration has medication before steroids and antiemetic；Treat every 21 days weights It is multiple.
Primary efficacy endpoint is the life that gets nowhere for the blind Radiologic evaluations based on response that guide is responded using RECIST It deposits the phase (PFS).Secondary result measurement includes following：(1) patient survival as secondary efficacy endpoint；(2) it is based on research people The progression free survival phase of member's assessment；(3) patient populations (%) of objective confirmation completely or partially responded are realized；(4) disease is steady Fixed >=16 weeks or all or part of patient populations (%) for responding (that is, total regression) and being identified；(5) response of response patient continues Time；(6) relationship of SPARC and other molecular biomarkers and efficacy results；(7) treatment is promptly and treatment-related bad The incidence of event (AE) and serious adverse events (SAE)；(8) laboratory abnormalities phenomenon；(9) bone during drug medication is studied Marrow inhibits minimum point；(10) change of patient experience research drug dose, dosing interruptions and/or the incidence stopped too early；(11) Pharmacokinetic parameter --- maximum plasma drug concentration (Cmax), plasma concentration vs time graphs area under (AUC and AUCinf), the half-life period (T1/2) of the apparent terminal phase portion of concentration vs time graphs, total systemic clearance (CL) and volume of distribution (Vz)。
The patient of selected research must be 18 years old or more.Male and female are suitable for studying.
Inclusion criteria includes：(1) skin malignant melanoma that histology or cytology confirm, there is transfer sign (IV ranks Section)；(2) cytotoxic chemotherapy without preceding for metastatic malignant melanoma (allow preceding kinase inhibitor or Cytokine therapy)；(3) (allow preceding interferon, GM-CSF and/or epidemic disease without preceding auxiliary cell cytotoxic chemical therapy Seedling complementary therapy)；(4) male or non-pregnancy and non-lactation period women >=18 year old；(5) current without other within past 3 years Active malignant tumour；(6) (for example, measurable disease can refer to, there are at least one radiation for the measurability disease of recorded radiation image Photologging surveys lesion)；(7) patient counts with following baseline blood：(a)ANC≥1.5x 109Cell/L；(b) blood Platelet >=100x 109Cell/L；(c)Hgb≥9g/dL；(8) patient has following baseline blood chemistry horizontal：(a)AST (SGOT), ALT (SGPT)≤2.5x normal range (NR)s lower limit (ULN) (≤5.0x ULN, if there is hepatic metastases)；(b) total courage is red Element≤ULN；(c) creatinine≤1.5mg/dL；(d)LDH≤2.0ULNa；(9) patient has>12 weeks expection life cycles；(10) suffer from Person has the performance state of 0-1；(11) patient or his/her legal authorization representative or guardian understand the essence of research, agree to Research is participated in, and informed consent form is signed before participating in any research correlated activation.
Go out to select the standard include：(1) medical history of brain metastes or current sign, including leptomeninges involve；(2) patient has and first deposits Scale >=2 grade NCI CTCAE peripheral nerve disease；(3) only in the case where lesion after the completion of radiation has clearly progress, Allow the preceding radiation to target lesion；(4) disease is clinically significantly synchronized；(4) research can not be completed until research Terminate (EOS) to access；(5) currently it is selected in different clinical researches, wherein carrying out the property investigated treatment procedure when participating in this research Or give investigation sex therapy；(6) it is related to any major organ systems so that researcher thinks that patient receives experimental research medicine Object is unsafe serious medical factor.
Embodiment 3：Nab- taxolsThe I phases of hepatic arterial infusion in hepatic metastases melanoma patient Research
This is the I phase dose escalatings research of open-label, is being given by day arteria hepatica of every three Monday with determiningThe responsiveness of hepatic metastases melanoma when treatment.Secondary purpose is to determine duration of response in liver, life cycle (Overall survival or progression free survival phase) and safety.
Meet and all be selected in/goes out to select the patient of standard to enter 3 to 6 groups, primary receiving in every 21 daysPerfusion. Maximum tolerated dose is determined after studying treatment cycle at two.Dose-limiting toxicity is defined as：>=3 grades of non-blood toxicity (or receive>The best symptomatic treatment of 3 grades of Nausea and vomitings or diarrhea), any 4 grades of transaminases increase (transaminitis), 3 grades of Neutrophilic granulocytopenias are with fever --- the parenteral that needs to be admitted to hospital takes antibiotic, 4 grades of Neutrophilic granulocytopenias continue >= 7 days or be complicated by infection or platelet count<25,000/mm3.Utilize 3.0 editions classification treatment poison of NCI Common Toxicity Criterias (CTC) Property.Treatment response is measured using RECIST.Investigate four kinds of dosage levels：130mg/m2、170mg/m2、220mg/m2And 285mg/ m2；These passed through hepatic arterial infusion in every three weeks through 30 minutes.
Embodiment 4：Filling type Nab- taxols weeklyThere is unresectable and metastatic grape The II phases in film melanoma patient are studied
This is to study the II phases, is determined in the treatment of metastatic uveal melanoma to single medicament Nab- taxolsWhole Response rate.Secondary purpose is to determine middle position progression free survival phase and Overall survival.Inclusion criteria is： (1) metastatic/unresectable uveal melanoma sign that histology or cytology confirm；(2) measurable disease --- quilt It is defined as at least one lesion that at least one size can be accurately measured and pass through CT scan >=10mm；(3) age >=18 years old or more；(4) it is 0 or 1 that ECOG, which shows state,；(5) without known HIV or hepatitis B or hepatitis C；(6) normal Organ/marrow function --- pass through following restriction：(a) Absolute Neutrophil Count >=1.5X 109/L；(b) blood platelet >= 100,000×109/L；(c) hemoglobin >=9.0gm/100mL；(d) total bilirubin≤1.5；(e) AST and ALT≤2.5X ULN；(f) creatinine≤1.8mg/mL；(g) in serum albumin levels timing calcium≤12mg/dL；(h) up to a kind of preceding Constitutional treatment.Going out to select standard is：(1) chemotherapy or radiotherapy in first 4 weeks are studied in entrance；(2) while receiving other and grind Study carefully medicament；(3) (basal cell cancer or other cancers are treated preceding malignant tumour, and patient has disengaged from disease two Except year)；(4) severe infections or other uncontrolled medical conditions；(5) notable mental disease；(5) pregnant；(6)>2 grades of week Enclose neuropathy.3 weeks in every 4 weeks 28 days are weekly with 150mg/m2Dosage by intravenous bolus doses through 30 Minute is given.
Embodiment 5：First gamma therapy of unresectable IV stages metastatic malignant melanoma (BRAF V600E are negative) AB (Add bevacizumab) it compares her and studies the randomization II phases of the wooden monoclonal antibody
This and current medical standard items she the wooden monoclonal antibody be comparedBevacizumab (AB) is added to combine Two groups of the randomization of effect of the scheme in carrying out the patient of the first gamma therapy of metastatic melanoma (BRAF V600E are negative) The Formula II phase is studied.The primary purpose of this research is that assessment is used as the first gamma therapyAdd the combination of bevacizumab Whether relative to her the wooden monoclonal antibody state that gets nowhere in unresectable IV stages melanoma patient is extended.Primary endpoint is nothing Be in progress life cycle, be defined as from be randomized to RECIST standards (version 1.1) limit earliest progress record or nothing into Time dead caused by any reason in the case of exhibition record.Secondary endpoints include Overall survival (from being randomized to any original The dead time caused by) and tumour response (v.1.1 using RECIST standards).
Relevant purpose is to investigate following variation：The biomarker (A groups) of angiogenesis and immune biomarker Object (A groups and B groups), and investigate the pharmacokinetics of taxol when being combined with bevacizumab therapy.Determine following blood vessel Generate the blood plasma level of intermediary：Angiopoietin-2, BMP-9, EGF, Endoglin, endothelin -1, FGF-1, FGF-2, Follistatin, G-CSF, HB-EGF, HGF, IL-8, leptin, PLGF, VEGF-A, VEGF-C and VEGF-D.Around analysis The T cell of blood sample (before all cycle therapies), the quantity and state of activation of B cell, NK cells and dendritic cells, and also Analyze CD3, CD4, CD8, CD20, CD69, CD4/25, CD8/25, CD16/56, CD80, CD86 and HLA- of peripheral blood samples DR。
Inclusion criteria is：(1) can not surgical excision IV stage chromomas Histological Evidence；(2) nothing, which is directed to, turns Move property melanoma in preceding constitutional treatment；(3) BRAF V600E wild-type mutants are not detected in metastatic tumo(u)r sample；(4) Measurable disease --- be defined as its longest diameter can be accurately measured as by chest X-ray >=2.0cm or by CT scan, At least one lesion of MRI scan or the CT part >=1.0cm of PET/CT scannings；(5) life expectancy >=4 month；(6) age >= 18 years s；(7) ECOG performances value is 0 or 1；(8) before registration or randomization≤14 days obtain following experiments number of chambers value：(a) ANC≥1500mL；(b) platelet count >=100,000x 109/L；(c) hemoglobin >=9g/dL；(d) creatinine≤1.5X ULN；(e) total bilirubin≤1.5mg/dL；(f)SGOT(AST)≤2.5X ULN；(g) albuminuria is not present when screening；(h) have The Serum Pregnancy test of the women of fecundity is negative；(i) it is suitably taken within 12 weeks during testing and after research drug is finally one Contraception；(j) informed consent form is signed.
Going out to select standard is：(1) brain metastes are accredited as according to MRI or CT；(2) before registering≤use other investigation type medicines within 4 weeks Agent；(3) before registering≤use any anti-cancer therapies within 4 weeks；(4) her the wooden monoclonal antibody or Japanese yew methane series chemotherapeutic treatment protocols are utilized before Or interrupt the pharmaceutical treatment of VEGF activity or targeting VEGFR；(5) register before≤4 weeks major surgical programs, style of opening biopsy It looks into or notable traumatic injury；(6) other medical conditions；(7) there is esthesionosis >=2 around (any reason causes)； (8) before being randomized≤2 weeks radiotherapy of taking stopgap measures；(9) before registering≤spit blood within 30 days behavior or nearly history；(10) known single to her wood Anti-, bevacizumab orArbitrary component have hypersensibility；(11) inflammatory bowel disease history is (for example, Crow grace ulcer Property colitis)；(12) patient of the diagnosis with autoimmune disease, no matter whether it was receiving treatment at that time in registration； (13)；Before registration≤2 weeks whole bodies use corticosteroid, whatsoever indication.
Table 5 and 6 describes two groups of this research.
5. A groups of table：Bevacizumab
6. B groups of table：Her wooden monoclonal antibody
Embodiment 6：Her is added to study II phase of the wooden monoclonal antibody in metastatic melanoma patient
This is to study the single group II phases of open-label, and determination is had the pernicious melanocyte of metastatic without chemotherapy by intravenous administration The patient's of tumorThe effect of her the wooden monoclonal antibody combination and safety.Primary purpose is to determineWith The combination of her the wooden monoclonal antibody whether the progression of disease of Branch-delay melanoma patient, and when determining 6 months Add the Progression free survival rate of her the wooden monoclonal antibody combination.Secondary purpose is：(1) it determinesHer is added the wooden monoclonal antibody combination to exist There is the effect in the patient of the unresectable III/IV stages melanoma of metastatic --- by whole and part responsiveness, response Duration and Overall survival measure；(2) it determinesAdd the combination of her the wooden monoclonal antibody by intravenous administration to control Treat safety when metastatic melanoma patient；(3) research receives the immunological changes of the patient of this therapy.
This experimentInitial dose be 150mg/m2, it is given within the 1st, 8 and 15 day at every 28 days.Medication and prevent without G-CSF through about 30 minutes by intravenous administration, before no steroids.Her wood of this experiment Monoclonal antibody dosage is intravenous 3mg/kg, only 4 doses every 3 weeks；Her the wooden monoclonal antibody of this dosage will not be increased.
Inclusion criteria is：(1) there is the histology of stage in late period IV or unresectable III stages mucous membrane or cutaneous melanoma The diagnosis of record；(2) melanoma (recurred) repeatedly, disease site can be surveyed or can estimate, 1.0cm or longer, with by immune Relevant response criteria (irRC) assessment treatment response；(3) it is directed to using cytotoxic drug and immunotherapeutic agent without preceding The treatment of unresectable III stages or IV stage diseases；(4) patient is between 12 and 70 years old, and ECOG performance states are 0 Or 1；(5) normal blood counts, and wherein white blood cell count is greater than or equal to 3000/mm3, Absolute Neutrophil Count is big In or equal to 1500mm3, and platelet count is more than 100,000/mm3, hemoglobin>9.0g/dL, absent renal function damage (female Property serum creatinine be less than 1.1mg/dL, male be less than 1.4mg/dL), (abnormal level of serum total bilirubin is less than no liver dysfunction 1.5mg/dL, AST and ALT≤2.5X ULN, unless there are hepatic metastases, AST and ALT≤5ULN are acceptable in this case), And without notable heart or pulmonary dysfunction sign；(6) such as persistently relevant more than 24 hours with fever without significantly synchronous disease Need the active infection of antibiotic, uncontrolled mental disease, hypercalcinemia (calcium is more than 11mg) or active hemorrhage of gastrointestinal tract； (7) there is the women of fecundity that must take acceptable contraception, and before the treatment for starting based on this experiment in 72 hours Serum or urine pregnancy test are negative and property enlivens male must also take contraceptive device during research；(8) signature is known Letter of consent.
Going out to select standard is：(1) metastatic uveal melanoma；(2) only Bone tumour；(3) symptomatic brain or spinal cord transfer, class Sterol is treated or leptomeninges (soft spinal meninges) disease；(4) notable heart disease；(5) chronic bronchitis, wind-puff or chronic obstructive Notable impairment of pulmonary function caused by lung disease --- cause the lung capacity of FEV1 to weaken to less than be expected the 75% of normal value；(6) Pleura, pericardium or the caused symptomatic exudation of peritonaeum transfer of melanoma；(7) non-generic cutaneum carcinoma --- substrate in past 3 years And squamous cell carcinoma --- Second malignant tumors history；(8) when baseline >=2 grades of esthesionosises.
Although some details of foregoing invention are described by example and example to be clearly understood that, the description It is not necessarily to be construed as limiting the scope of the invention with embodiment.

Claims (43)

1. including that the composition of the nano particle containing taxol and albumin is being prepared for treating people in need thereof Application in the drug of the melanoma of body, wherein being selected based on the individual with the melanoma including the V600E mutation in BRAF The individual is selected to be treated.
2. application according to claim 1, wherein the individual based on the metastatic melanoma with the M1c stages, comes The individual is further selected to be treated.
3. application according to claim 1, wherein had based on the individual be more than 1.1 × to the blood between 2.0 × ULN Clear LDH is horizontal, further to select the individual to be treated.
4. application according to any one of claim 1-3, wherein the application further comprises the second therapy.
5. application according to claim 4, wherein the application includes giving at least one other therapeutic agents.
6. application according to claim 5, wherein the other therapeutic agents are BRAF inhibitor.
7. application according to claim 5, wherein the other therapeutic agents are her wooden monoclonal antibodies.
8. application according to any one of claim 1-3, wherein the application is used as the first gamma therapy.
9. application according to any one of claim 1-3, wherein the application is used as the second gamma therapy.
10. application according to any one of claim 1-3, wherein described includes the nanometer containing taxol and albumin The composition of particle is by intravenous administration.
11. application according to any one of claim 1-3, wherein in the Nanoparticulate compositions taxol dosage For 80mg/m2To 200mg/m2。
12. application according to claim 11, wherein the dosage of taxol is 150mg/ in the Nanoparticulate compositions m2。
13. application according to any one of claim 1-3, wherein described includes the nanometer containing taxol and albumin The composition of particle is given weekly.
14. application according to claim 13, wherein described includes the group of the nano particle containing taxol and albumin Close object being given for the 1st, 8 and 15 day in 28 days treatment cycles.
15. application according to any one of claim 1-3, wherein the albumin is human serum albumins.
16. application according to any one of claim 1-3, wherein the average diameter of nano particle is not in the composition More than 200nm.
17. application according to claim 16, wherein in the Nanoparticulate compositions albumin and taxol weight Than being 9：1 or smaller.
18. application according to claim 17, wherein in the Nanoparticulate compositions albumin and taxol it is described Weight ratio is 9：1.
19. application according to claim 16, wherein the taxol in the nano particle is coated with the albumin.
20. application according to claim 16, wherein in the Nanoparticulate compositions albumin and taxol weight Than being 9：1 or smaller, and the taxol in the wherein described nano particle is coated with the albumin.
21. application according to any one of claim 1-3, wherein albumin and Japanese yew in the Nanoparticulate compositions The weight ratio of alcohol is 9：1 or smaller.
22. application according to claim 21, wherein the taxol in the nano particle is coated with the albumin.
23. according to claim 1-3 any one of them applications, wherein albumin and taxol in the Nanoparticulate compositions Weight ratio be 9：1.
24. application according to claim 23, wherein the taxol in the nano particle is coated with the albumin.
25. application according to any one of claim 1-3, wherein the taxol in the nano particle be coated with it is described Albumin.
26. application according to claim 5, wherein the application is used as the first gamma therapy.
27. application according to claim 5, wherein the application is used as the second gamma therapy.
28. application according to claim 5, wherein described includes the combination of the nano particle containing taxol and albumin Object is by intravenous administration.
29. application according to claim 5, wherein the dosage of taxol is 80mg/m in the Nanoparticulate compositions2Extremely 200mg/m2。
30. application according to claim 29, wherein the dosage of taxol is 150mg/ in the Nanoparticulate compositions m2。
31. application according to claim 5, wherein described includes the combination of the nano particle containing taxol and albumin Object is given weekly.
32. application according to claim 31, wherein described includes the group of the nano particle containing taxol and albumin Close object being given for the 1st, 8 and 15 day in 28 days treatment cycles.
33. application according to claim 5, wherein the albumin is human serum albumins.
34. application according to claim 5, wherein the average diameter of nano particle is not more than 200nm in the composition.
35. application according to claim 34, wherein in the Nanoparticulate compositions albumin and taxol weight Than being 9：1 or smaller.
36. application according to claim 35, wherein in the Nanoparticulate compositions albumin and taxol it is described Weight ratio is 9：1.
37. application according to claim 34, wherein the taxol in the nano particle is coated with the albumin.
38. application according to claim 34, wherein in the Nanoparticulate compositions albumin and taxol weight Than being 9：1 or smaller, and the taxol in the wherein described nano particle is coated with the albumin.
39. application according to claim 5, wherein in the Nanoparticulate compositions albumin and taxol weight ratio It is 9：1 or smaller.
40. application according to claim 5, wherein in the Nanoparticulate compositions albumin and taxol weight ratio It is 9：1.
41. application according to claim 39, wherein the taxol in the nano particle is coated with the albumin.
42. application according to claim 40, wherein the taxol in the nano particle is coated with the albumin.
43. application according to claim 5, wherein the taxol in the nano particle is coated with the albumin.
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